- Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy
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Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.
- Ashcraft, Luke,Chin, Eva R.,Chuang, Chihyuan,Collibee, Scott,Cremin, Peadar,Hartman, James,Hwee, Darren T.,Malik, Fady I.,Morgan, Bradley P.,Robertson, Laura A.,Schaletzky, Julia,Vander Wal, Mark,Wang, Jingying,Wang, Wenyue,Wang, Xiaolin,Wehri, Eddie,Wu, Yangsong,Zamora, Jeanelle
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supporting information
p. 14142 - 14152
(2021/10/20)
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- DIHYDROBENZOFURAN AND INDEN ANALOGS AS CARDIAC SARCOMERE INHIBITORS
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Provided are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A, Z, B, R1, R2, R3, G1, G2, and G3 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt, thereof for use in methods of treatment heart diseases through cardiac sarcomere inhibtion.
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Paragraph 0383
(2019/08/08)
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- USE OF GHRELIN RECEPTOR INVERSE AGONISTS OR ANTAGONISTS FOR TREATING SLEEP DISORDERS
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The present invention relates to methods of treating sleep disorders in patients comprising administration of a ghrelin receptor inverse agonist or antagonist. The invention also includes methods of treating sleep disorders comprising the administration of a pharmaceutical composition comprising a ghrelin receptor inverse agonist or antagonist and at least one pharmaceutically acceptable carrier, diluent, or excipient.
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Page/Page column 17
(2014/01/08)
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- 2,3-DIHYDRO-1H-INDEN-1-YL-2,7-DIAZASPIRO[3.5] NONANE DERIVATIVES
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The present invention provides a compound of Formula (I) or a pharmaceutically salt thereof wherein R1, R2, Ra, L, Z, Z1 and Z2 are as defined herein, that act as Ghrelin antagonists or inverse agonists; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by the antagonism of the Ghrelin receptor.
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Page/Page column 25
(2011/10/10)
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