Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin
| Autor: | Sang-Hun Jung, Niti Sharma, Pulla Reddy Boggu, Eeda Venkateswararao, Jong Seong Kang, Manoj Manickam |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
ATPase Clinical Biochemistry Pharmaceutical Science 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Myosin Humans Isoxazole Amines Molecular Biology Adenosine Triphosphatases biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Activator (genetics) Organic Chemistry Tetrahydropyran Isoxazoles 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry biology.protein Molecular Medicine Amine gas treating Piperidine Bioisostere Cardiac Myosins |
| Zdroj: | Bioorganicmedicinal chemistry. 28(22) |
| ISSN: | 1464-3391 |
| Popis: | To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4–7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 µM = 81.6%), 4w (CMA at 10 µM = 71.2%) and 6b (CMA at 10 µM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 µM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure–activity relationship (SAR) studies were conducted. Para substitution (-Cl, –OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 µM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure. |
| Databáze: | OpenAIRE |
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