Reviews: 2017 Medicinal Chemistry Reviews

1. Introduction 3

2. Strategy for Drug Screening 5

3. Hit Identification and Strategy for Chemistry 6

4. Candidate Identification 7

5. Characterization of Compounds 6e and 7b 15

5.1 PDE10A Selectivity and PK Profile of 6e and 7b 15

5.2 In Vivo Pharmacological Profile of 6e and 7b 15

5.3 Safety Profile of 7b 18

6. Conclusions 19

1.          Introduction                                                                                                               25

2.         Vinpocetine and Early Non-Selective PDE1 Inhibitors                                           28

3.         Recent Medicinal Chemistry and Pharmacology of Selective PDE1 Inhibitors  29

4.         PDE1 Structural Biology                                                                                             33

5.         Patent Landscape                                                                                                     35

            5.1        Fused 6,5-Bicyclic Rings                                                                                35

            5.2       Fused 6,6-Bicyclic Rings                                                                                37

            5.3       Fused Tricyclic Rings                                                                         37

6.         Conclusions                                                                                                               38

1.          Introduction                                                                                                               45

2.         Next-Generation ALK Program—Acyclic (or Non-Macrocyclic) 

            Chemical Space                                                                                                         48

3.         Macrocyclic Inhibitors—Discovery of Lorlatinib (16)                                             51

4.         Selectivity Strategy                                                                                                    54

5.         CNS Exposure                                                                                                            57

6.         Acyclics versus Macrocycles                                                                          60

7.         Overview of Lorlatinib (16)                                                                                       61

1.          Introduction                                                                                                               69

2.         Overview of GPCR Structural Biology Approaches                                                 72

3.         Overview of Orthosteric Structures of CNS GPCRs                                                 74

4.         Allosteric Modulation of CNS GPCR Targets                                                           80

5.         Conclusions

1.          Introduction                                                                                                               89

2.         BACE1 and the Amyloid Hypothesis                                                                        90

3.         Safety and Tolerability of BACE Inhibition                                                             91

            3.1        Bace1 Knockout Mice                                                                                    91

            3.2       Bace2 Knockout Mice                                                                                    92

            3.3       Cathepsin D                                                                                                   93

4.         Compounds in Advanced Clinical Development                                                   94

            4.1        Verubecestat                                                                                      94

            4.2       Lanabecestat, Elenbecestat, JNJ54861911, CNP520                                   97

5.         Conclusions                                                                                                               101

1.          Introduction                                                                                                               109

            1.1        Introduction to Heart Failure (HF)                                                               109

            1.2        Basic Cardiac Sarcomere Muscle Biology                                                    111

2.         Increasing Cardiac Contractility: An Approach to HFrEF                                       112

            2.1        Early Approaches to Cardiac Sarcomere Activation                                   112

            2.2       Current Approaches to Cardiac Sarcomere Activation                              114

3.         Selective Cardiac Myosin Activators                                                                        115

            3.1        Omecamtiv Mecarbil                                                                                     115

                        3.1.1     Omecamtiv Mecarbil: Optimization                                                 115

                        3.1.2     Omecamtiv Mecarbil: Mechanism of Activation Studies               117

                        3.1.3     Omecamtiv Mecarbil: In Vivo Proof of Concept                            118

            3.2       MYK-491                                                                                                         118

4.         Clinical Progress of Cardiac Sarcomere Activators                                                 118

            4.1        Levosimendan                                                                                               119

            4.2       Pimobendan                                                                                                  119

            4.3       Omecamtiv Mecarbil                                                                                     119

5.         Conclusions                                                                                                               120

1.          Introduction                                                                                                               125

2.         Early Discovery of Intestinal Sodium-Dependent Phosphate 

            Transporter Inhibitors                                                                                              127

3.         Investigation of Sodium-Dependent Phosphate Co-Transporter 2b

 Inhibitors                                                                                                                  130

            3.1        Triazoles                                                                                                         131

            3.2       Acylhydrazones                                                                                             132

            3.3       Thiophene Amides                                                                                        133

            3.4       Anthranilic Amides and Related Analogs                                                   136

            3.5       Dihydropyridazine-3,5-diones                                                                     141

4.         Clinical Studies and Future Perspectives                                                     142

1.          Introduction                                                                                                               147

            1.1        Introduction to Diabetes                                                                              147

            1.2        Glucokinase                                                                                                    147

2.         Glucokinase Activators                                                                                              149

            2.1        Background                                                                                                    149

            2.2       Selected GKA Publications Prior to 2014                                                     150

            2.3       Selected GKA Publications After 2014                                                          153

                        2.3.1     Liver-Selective GKAs                                                              153

                        2.3.2    Novel “Carbon-Centered” GKAs                                                      154

                        2.3.3    Novel “Aromatic-Centered” GKAs                                                   154

3.         Conclusions                                                                                                               157

1.          Introduction                                                                                                               165

            1.1        CSF1R as an Immunological Target                                                  165

            1.2        Role in Disease Pathology                                                                           166

            1.3        Potential Concerns Associated with Inhibition                                         167

2.         Recent Small-Molecule CSF1R Inhibitors                                                     168

            2.1        Heteroarylamides                                                                                          168

            2.2       Amidoquinolines and Amidocinnolines                                                     170

            2.3       Other Chemotypes                                                                                        171

3.         Clinical Data                                                                                                               173      

4.         Conclusions                                                                                                               174

1.          Introduction                                                                                                               179

2.         Ileal Bile Acid Transporter (IBAT) Inhibitors                                                           180

3.         TGR5 Agonists                                                                                                            182

4.         Pan JAK Inhibitors                                                                                                    183

5.         “Narrow Spectrum” Tyrosine Kinase Inhibitors                                                     184

6.         RET Kinase Inhibitors                                                                                                185

7.         α4-β7 Integrin Antagonist (PTG-100)                                                                       185

8.         NHE3 Inhibitors                                                                                                         187

9.         F₁F₀-ATPase Modulator                                                                                             188

10.        Summary/Lessons Observed                                                                                    189

1.          Introduction                                                                                                               195

            1.1        The ROR Family                                                                                             196

            1.2        Structure of RORγ and Endogenous Ligands                                              196

            1.3        Expression and Function of RORγ and RORγt                                           198

                        1.3.1     RORγt Master Regulator of T_H17 and Other Immune Cells            198

                        1.3.2     RORγ Functions in Non-Immune Cells                                            199

2.         Role of RORγt in Disease                                                                                          199

            2.1        Autoimmune Diseases                                                                                  199

            2.2       Other Indications                                                                                          201

3.         Small-Molecule Modulators of RORγt                                                                     202

            3.1        Ligands of the Canonical Binding Pocket                                                  202

                        3.1.1     Hexafluoroisopropanols                                                                  202

                        3.1.2     Tertiary Sulfonamides                                                                       202

                        3.1.3     Sulfonamides of Cyclic Amines                                                        204

                        3.1.4     Biaryls                                                                                                 205

                        3.1.5     Alkylsulfonylbenzyl Compoundslls                                                 206

                        3.1.6     Piperazines                                                                                        207

                        3.1.7     Miscellaneous Compounds                                                              208

            3.2       Allosteric Ligands                                                                                          209

4.         Clinical Development of RORγt Modulators                                                          211

5.         Conclusions                                                                                                               212

1.          Introduction                                                                                                               221

2.         IDO and TDO Enzymes                                                                                              222

3.         Toll-Like Receptors                                                                                        223

4.         Adenosine Pathway                                                                                     224

5.         Arginine Metabolism                                                                                                226

6.         PGE2                                                                                                                           227

7.         Chemokines and Chemokine Receptors                                                                227

            7.1        CXCR1/CXCR2                                                                                     228

            7.2       CXCR4                                                                                                 229

            7.3       CCR5                                                                                                               230

            7.4       CCR2                                                                                                               230

            7.5       CCR4                                                                                                               231

8.         Kinases                                                                                                                       232

9.         Conclusion                                                                                                                 234

1.          Introduction                                                                                                               244

            1.1        The DNA Damage Response (DDR) in Cancer—Complexity and

Redundancy                                                                                                   244

            1.2        Exploiting the DDR to Date—the PARP Inhibitors                                                245

            1.3        Challenges for Drug Discovery                                                                     245

                        1.3.1     Druggability of Emerging Target Classes                                         245

                        1.3.2     Biological and Screening Challenges                                              246

2.         DDR-Related Kinases                                                                                                247

            2.1        ATM and ATR Kinases—Similarities and Differences                                247

            2.2       ATM Inhibitors                                                                                               248

            2.3       ATR Inhibitors                                                                                                249

            2.4       Clinical Progression                                                                                      251

3.         Exploiting Compromised DDR via Wee1 Kinase                                                    252

            3.1        Wee1 Inhibitors                                                                                             252

            3.2       Single Agent vs. Combination Studies Reveal Novel Therapeutic

Options                                                                                                          253

            3.3       Clinical Progression                                                                                      254

4.         PARG Inhibitors                                                                                                         254

            4.1        The Role of PARG                                                                                          254

            4.2       PARG Inhibitors                                                                                             255

            4.3       Clinical Implications                                                                                      256

5.         Future Directions and Conclusions                                                                          257

1.          Introduction                                                                                                               263

2.         Small-Molecule Selective Mcl-1 Antagonists                                                            266

            2.1        AMG 176                                                                                                         266

            2.2       S63845                                                                                                           267

            2.3       AZD5991                                                                                                         269

            2.4       Indole-2-carboxylate Inhibitors                                                                   270

            2.5       Indole-2-(methylsulfonyl)carboxamide Inhibitors                                                 272

            2.6       Arylboronic Acid Covalent Inhibitors                                                          273

            2.7       Cyclopeptidic Inhibitors                                                                               274

3.         Conclusions                                                                                                               275

1.          Introduction                                                                                                               281

2.         Critical Medicinal Chemistry Objectives                                                                  284

3.         Approaches to Targeting Gram-Positive Pathogens                                              286

            3.1        Oxabicyclooctane Linkers                                                                            286

            3.2       Tetrahydropyran Linkers                                                                              287

            3.3       Carboxypiperidine Linkers                                                                           288

            3.4       Aminopiperidine Linkers                                                                              289

4.         Approaches to Targeting Gram-Negative Pathogens                                             290

            4.1        Aminocyclohexane Linkers                                                                          290

            4.2       Tetrahydropyran Linkers                                                                              292

            4.3       Fused Tricyclic DNA-binding Moieties                                                         293

5.         Pharmacokinetic/Pharmacodynamic Relationships                                              293

6.         Clinical Trials                                                                                                              295

7.         Conclusions                                                                                                               296

1.          Introduction                                                                                                               305

            1.1        Hepatitis B Overview                                                                                    305

            1.2        Capsid Biology                                                                                              306

2.         Capsid Assembly Modulator Chemotypes                                                             307

            2.1        Heteroaryl Pyrimidines                                                                                 307

            2.2       Sulfonyl Carboxamides                                                                                309

            2.3       Others                                                                                                 311

3.         Mechanism of Action                                                                                                312

4.         In Vivo Preclinical Studies and Emerging Clinical Data with

Capsid Assembly Modulators                                                                                  314

5.         Concluding Remarks                                                                                     315

1.          Introduction                                                                                                               319

2.         New Mindsets In Antibacterial Development                                                        321

            2.1        Disparate Membrane Polarity in Gram-Negatives                         321

            2.2       Chemical Space and Structural Uniqueness of Gram-Negative

Actives                                                                                                            322

            2.3       Enhanced Antibacterial Potency                                                                 322

            2.4       Early Consideration of Combinatorial Therapy                                         322

            2.5       Development of Narrow-Spectrum Therapeutics                           323

            2.6       Non-Traditional Approaches to Antibacterial Development                    323

3.         Methods to Evaluate Antibacterial Activity                                                            323

            3.1        Chemical Modification of Cells                                                                    324

            3.2       Genetic Modification of Cells                                                                       325

4.         Methods to Determine Compound Permeation and Accumulation                    325

            4.1        Mass Spectrometry                                                                                       326

            4.2       Fluorescence                                                                                      326

            4.3       Electrophysiology and Liposome Swelling Assays                                    326

5.         Recent Examples of Rational Approaches to Enhance

Gram-Negative Accumulation                                                                                   328

            5.1        Sulfamoyladenosines                                                                                   329

            5.2       Oxazolidinones                                                                                             330

            5.3       Tetrahydropyran-Based Topoisomerase Inhibitors                                   332

            5.4       Diverse Chemotype Analysis                                                                       333

6.         Conclusion                                                                                                                 334

1.          Introduction                                                                                                               343

2.         Oligomers                                                                                                                   344

3.         Ions                                                                                                                             348

4.         Peptides                                                                                                                     351

5.         Amino Acids                                                                                                               352

6.         Purinergic Nucleotides                                                                                              353

7.         Carbohydrates                                                                                                           353

8.         Lipids                                                                                                                          354

9.         Metabolites of Orthosteric Ligands                                                             355

10.        Summary: Implications in Drug Design                                                                   357

1.          Introduction                                                                                                               363

2.         Thinking Small: Optimization of the Linker-Payload                                            364

            2.1        Advancing New Linker-Cleavage Mechanisms                                           364

            2.2       Understanding the Released Species                                                          367

            2.3       Optimizing the Linker Stability                                                                    370

3.         Dreaming Big: Optimization of the Bioconjugate                                                  373

            3.1        The Impact of the Linker-Payload on the Biophysical Properties 

                        of the ADC                                                                                                     373

            3.2       The Impact of Conjugation Site on the Stability of the Linker Payload  375

4.         Conclusions and Future Outlook                                                                             379

1.          Introduction                                                                                                               383

            1.1        Overview                                                                                                        383

            1.2        Proteomics Approaches to Understanding Biological Function              385

                        1.2.1     SILAC                                                                                      385

                        1.2.2     Isobaric Tagging-Coupled Mass Spectrometry                               385

2.         SILAC Analysis Strategies                                                                              386

            2.1        SILAC Labeling and Global Proteome Analysis in Cultured Cells             386

            2.2       Application of SILAC to Analysis of Post-Translational Modifications 

                        and Protein Interaction Networks                                                               387

            2.3       SILAC Strategies for Whole Animal and Human Studies               392

3.         SILAC Proteomics in Drug Discovery                                                                       393

            3.1        Target Discovery and Pathway Biology                                                      393

            3.2       Compound Mechanism of Action                                                               395

            3.3       Biomarker Discovery                                                                         398

4.         Limitations of SILAC                                                                                                 398

5.         Conclusions                                                                                                               398

1.          Introduction                                                                                                               405

2.         Extensive Metabolism Observed During Clinical Trials                                         406

3.         Structure and Function of Aldehyde Oxidase                                                         408

            3.1        Structural and Mechanistic Aspects                                                             408

            3.2       Substrate Scope                                                                                             409

4.         Variation in Structure, Function and Distribution                                                  410

5.         Identifying and Predicting Aldehyde Oxidase Metabolism                                  411

6.         Strategies to Attenuate Aldehyde Oxidase Metabolism                                        413

            6.1        Androgen Receptor Antagonists                                                                 413

            6.2       Toll-Like Receptor Antagonists                                                                    413

            6.3       Zoniporide Derivatives                                                                                 414

            6.4       Phosphatidylinositol 3-Kinase Inhibitors                                                   415

            6.5       Mesenchymal—Epithelial Transition Factor Inhibitors                             416

            6.6       Deuterium Incorporation: VX-984                                                               416

            6.7       Tropomyosin-Related Kinase Inhibitors                                                     417

7.         Conclusion                                                                                                                 417

1.          Introduction                                                                                                               423

2.         In Vitro Functional Screening of Remyelination                                                     425

            2.1        Phenotypic Assays of Remyelination                                                         426

3.         Targets and Repositioning Drugs for Remyelination                                            427

            3.1        Muscarinic Antagonists                                                                                 427

            3.2       Dopamine Modulators                                                                                 429

            3.3       Kappa Opioid Receptor Agonists                                                    431

            3.4       Endocannabinoid Ligands                                                                           432

            3.5       PDE7 Inhibitors                                                                                             434

            3.6       PPAR Receptor Agonists                                                                               434

            3.7       Miscellaneous Targets and Drugs                                                    435

4.         Conclusion                                                                                                                 437

1.          Introduction                                                                                                               443

2.         TRP Channel Structural Features and Gating                                                          444

            2.1        General TRP Architecture                                                                              444

            2.2       Specific Features of TRPV1, TRPA1, and TRPM8                                         445

            2.3       TRP Channel Gating                                                                                      447

            2.4       Ligand Binding Domains of TRPV1, TRPA1, and TRPM8                           447

3.         Modulators of TRPV1, TRPA1, and TRPM8                                                              449

            3.1        Physiological Impacts of Modulating TRPV1, TRPA1, and TRPM8            449

            3.2       Nonselective Natural TRP Channel Modulators                                         450

            3.3       Nonselective Synthetic Modulators                                                            453

            3.4       Selective Synthetic Modulators                                                                   454

4.         Conclusion                                                                                                                 460

1.          Introduction                                                                                                               465

2.         BSEP Deficiency and DILI                                                                                         466

3.         Inhibition of BA Transport as a Causative Factor for DILI                                     467

4.         Physicochemical Characteristics and Structure-Toxicity Relationships                470

            4.1        Nontricyclic Antidepressants                                                                       473

            4.2       Thiazolidinediones                                                                                       473

            4.3       Endothelial Receptor Antagonists (ERAs)                                                   475

5.         Prediction of DILI Risk                                                                                              477

6.         Conclusion                                                                                                                 479

1.          Introduction                                                                                                               485

2.         Mechanisms of the Disease                                                                                     486

3.         Discovery of Lesinurad                                                                                             488

4.         Scale-up Process Development                                                                                489

5.         Path to Regulatory Approval                                                                                   490

6.         Conclusion                                                                                                                 492

1.          Introduction                                                                                                               497

2.         Discovery of Chidamide                                                                                           498

            2.1        Identification of Chemical Scaffold Inhibiting HDACs                              498

            2.2       Medicinal Chemistry Efforts Aimed at the Discovery of New 

                        Selective HDAC Inhibitor                                                                              499

            2.3       Multiplicity of Anticancer Mechanism                                                         503

3.         Preclinical Profiles of Chidamide                                                                            504

4.         Clinical Development of Chidamide                                                                       506

            4.1        A Phase I Clinical Study                                                                                506

            4.2       Exploratory and Pivotal Phase II Clinical Studies on PTCL                       508

5.         Conclusions                                                                                                               510

Information for 44 drugs in Phase III Trials

1.          Atezolizumab (anticancer)                                                                                  537

2.         Beclabuvir (antiviral)                                                                                           539

3.         Bezlotoxumab (antibacterial)                                                                               541

4.         Brivaracetam (epilepsy)                                                                                       543

5.         Brodalumab (psoriasis)                                                                                        545

6.         Crisaborole (atopic dermatitis)                                                                             547

7.         Elbasvir (antiviral)                                                                                              549 

8.         Etelcalcetide (secondary hyperthyroidism)                                                            551

9.         Eteplirsen (Duchenne muscular dystrophy)                                                           553

10.        Evogliptin (diabetes)                                                                                           555

11.        Gosogliptin (diabetes)                                                                                         557

12.        Grazoprevir (antiviral)                                                                                         558

13.        Ixekizumab (psoriasis)                                                                                        560

14.        Lifitegrast (dry eye disease)                                                                                563

15.        Migalastat (Fabry disease)                                                                                    565

16.        Nusinersen (spinal muscular atrophy)                                                                    566

17.        Obeticholic Acid (primary biliary cholangitis)                                                           569

18.        Obiltoxaximab (antibacterial)                                                                                  571 

19.        Olaratumab (anticancer)                                                                                        572

20.       Olmutinib (anticancer)                                                                                            574

21.        Opicapone (Parkinson’s disease)                                                                             576

22.       Pimavanserin (Parkinson’s disease)                                                                          578

23.       Pitolisant (narcolepsy)                                                                                             580

24.       Reslizumab (asthma)                                                                                               581

25.       Rucaparib (anticancer)                                                                                             583

26.       Venetoclax (anticancer)                                                                                            585

27.       Velpatasvir (antiviral)                                                                                               587