Medicinal Chemistry Reviews

Volume 52, Chapter 6

Cardiac Sarcomere Activation and its Therapeutic Application in Heart Failure

Antonio Romero and Bradley P. Morgan

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

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