Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin |
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| Affiliation: | 1. College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, Republic of Korea;2. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea;1. Department of Chemistry, UCL, Christopher Ingold Building, 20, Gordon Street, London WC1H 0AJ, UK;2. Department of Structural and Molecular Biology, UCL, Gower Street, London WC1E 6BT, UK;3. Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK;1. Synthia LLC, Davis, CA 95616, United States;2. Department of Entomology and Nematology, One Shields Ave, University of California-Davis, Davis, CA 95616, United States;3. EicOsis Human Health, 140 B Street, Suite 5, Number 346, Davis, CA 95616, United States;1. Promega Biosciences, 277 Granada Drive, San Luis Obispo, CA 93401, USA;2. SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA;3. Department of Chemistry and Biochemistry, California Polytechnic State University, 1 Grand Ave., San Luis Obispo, CA 93407, USA;4. Department of Chemistry & Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA;5. RTI International, 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, NC 27709, USA;1. School of Life Science and Engineering, Handan University, Handan 056005, China;2. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China;3. Hebei Key Laboratory of Heterocyclic Compounds, College of Chemical Engineering and Materials, Handan University, Handan 056005, China;4. School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China;1. Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy;2. Section of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź Poland |
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| Abstract: | 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. |
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| Keywords: | Diphenylalkylisoxazol-5-amine Cardiac myosin ATPase activator SAR Systolic heart failure |
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