Journal of Medicinal Chemistry p. 11131 - 11148 (2020)
Update date:2022-08-15
Topics:
Brawley, Jhonnathan
Etter, Emily
Heredia, Dante
Intasiri, Amarawan
Nennecker, Kyle
Smith, Joshua
Welcome, Brandon M.
Brizendine, Richard K.
Gould, Thomas W.
Bell, Thomas W.
Cremo, Christine
Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation. The lead compound for this study ((3-(N-butylethanimidoyl)ethyl)-4-hydroxy-2H-chromen-2-one; BHC) was previously discovered to inhibit skeletal myosin II. BHC and 34 analogues were synthesized to explore structure-activity relationships. The properties of analogues, including solubility, stability, and toxicity, suggest that the BHC scaffold may be useful for developing therapeutics. Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity were measured. Several analogues with aromatic side arms showed improved potency (half-maximal inhibitory concentration (IC50) <1 μM) and selectivity (≥12-fold) for skeletal myosin versus cardiac myosin compared to BHC. Several analogues blocked neurotransmission, suggesting that they are selective for nonmuscle myosin II over skeletal myosin. Competition and molecular docking studies suggest that BHC and blebbistatin bind to the same site on myosin.
View MoreGUANGZHOU MEDCAN PHARMATECH LTD
website:http://www.gzmedcan.com
Contact:+86-20-82519649
Address:Building J,Room 101,1 JiangtashanRd,Guang Zhou Science City,Guang Zhou ,China
HANGZHOU ZHONGCHANG SCIENTIFIC CO.,LTD
Contact:+86-571-88932183
Address:Hangzhou
Contact:86-379-63338609
Address:Jiudian Village,Deting Town,Song County,Luoyang
suzhou BetterBioChem Co., Ltd.
website:http://www.betterbiochem.com
Contact:+86-18013506594
Address:No. 8 Building, 18 nong, Xi Yingnan Road, Pudong, Shanghai,China
Hangzhou GreenCo Science & Technology Co., Ltd.
Contact:86-571-88257303
Address:1713 Room,Jingui Building,Gudun Road,Xihu District,Hangzhou,China
Doi:10.1021/ja00515a022
(1979)Doi:10.1039/c4cc00914b
(2014)Doi:10.1021/jo01289a007
(1980)Doi:10.1021/jm00175a016
(1980)Doi:10.1021/ja01222a020
(1945)Doi:10.1002/anie.202012459
(2021)