دورية أكاديمية
أعرض في EDS

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

التفاصيل البيبلوغرافية
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.
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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
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c02413