دورية أكاديمية
Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.
العنوان: | Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility. |
---|---|
المؤلفون: | Romero A; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Ashcraft L; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Chandra A; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., DiMassa V; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Cremin P; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Collibee SE; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Chuang C; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Hartman J; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Hwee DT; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., St Jean D; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Malinowski J; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., DeBenedetto M; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Moebius D; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Payette J; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Vargas R; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Yeoman J; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Motani A; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Reagan J; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Malik FI; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States., Morgan BP; Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States. |
المصدر: | Journal of medicinal chemistry [J Med Chem] 2024 May 23; Vol. 67 (10), pp. 7825-7835. Date of Electronic Publication: 2024 May 10. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
مواضيع طبية MeSH: | Myocardial Contraction*/drug effects, Humans ; Animals ; Cardiovascular Diseases/drug therapy ; Rats ; Structure-Activity Relationship ; Male ; Drug Discovery ; Troponin/metabolism ; Mice ; Rats, Sprague-Dawley ; Sulfonamides/pharmacology ; Sulfonamides/pharmacokinetics ; Sulfonamides/chemistry ; Sulfonamides/therapeutic use ; Sulfonamides/chemical synthesis |
مستخلص: | Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv ( CK-136 ), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R , a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138 . Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development. |
References: | ACS Med Chem Lett. 2010 Aug 20;1(9):472-7. (PMID: 24900233) Cardiovasc Res. 1999 Apr;42(1):254-61. (PMID: 10435018) J Biomed Biotechnol. 2011;2011:486021. (PMID: 22131807) Circulation. 2018 Jan 30;137(5):508-518. (PMID: 29378757) J Med Chem. 2024 May 23;67(10):7859-7869. (PMID: 38451215) Br J Pharmacol. 2014 Dec;171(23):5169-81. (PMID: 24547784) Annu Rev Pharmacol Toxicol. 2011;51:145-67. (PMID: 21210745) N Engl J Med. 2021 Jan 14;384(2):105-116. (PMID: 33185990) ACS Med Chem Lett. 2021 Aug 10;12(9):1396-1404. (PMID: 34531948) Science. 2011 Mar 18;331(6023):1439-43. (PMID: 21415352) J Am Coll Cardiol. 2011 Nov 15;58(21):2241-7. (PMID: 22078432) Drug Metab Dispos. 1999 Nov;27(11):1350-9. (PMID: 10534321) Anesthesiology. 2006 Mar;104(3):556-69. (PMID: 16508404) J Muscle Res Cell Motil. 2012 Dec;33(6):403-17. (PMID: 22847802) Acc Chem Res. 2002 Nov;35(11):984-95. (PMID: 12437323) Card Fail Rev. 2019 Nov 04;5(3):133-139. (PMID: 31768269) Eur Heart J Cardiovasc Pharmacother. 2022 Jan 5;8(1):77-84. (PMID: 32976560) Nat Commun. 2017 Aug 4;8(1):190. (PMID: 28775348) Circ Heart Fail. 2022 Mar;15(3):e009195. (PMID: 34743528) Circulation. 2019 Apr 2;139(14):e801-e813. (PMID: 30586770) Eur Heart J Acute Cardiovasc Care. 2021 Aug 24;10(6):676-686. (PMID: 34219157) |
المشرفين على المادة: | 0 (Troponin) 0 (Sulfonamides) |
تواريخ الأحداث: | Date Created: 20240510 Date Completed: 20240523 Latest Revision: 20240529 |
رمز التحديث: | 20240529 |
مُعرف محوري في PubMed: | PMC11129190 |
DOI: | 10.1021/acs.jmedchem.3c02413 |
PMID: | 38729623 |
قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!