Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon. (1st November 2022)

• Record Type: Journal Article
• Authors: Zhang, Weihe; Vadlakonda, Satish; Wu, Minwan; Chintareddy, Venkat; Vogeti, LN; Juarez, Luis; Muppa, Saritha; Parker, Cynthia; Kellogg-Yelder, Debra; Williams, Jason; Polach, Kevin; Chen, Xilin; Raman, Krishnan; Babu, Y.S.; Kotian, Pravin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 73(2022)
• Publication Date: 2022-11-01
• Subjects: Hereditary angioedema -- HAE -- Plasma Kallikrein inhibitor -- PKal inhibitor -- HAE medicine -- Quaternary carbon -- Lead optimization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117035
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50, 000 individuals worldwide. Berotralstat (BCX7353 ) is the only small molecule approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, we also identified a novel series of small molecules containing a quaternary carbon as potent and orally bioavailable Plasma Kallikrein (PKal) inhibitors. Lead compound was identified as a potent inhibitor following a detailed lead optimization process that balanced the lipophilic efficiency (LipE) and pharmacokinetic (PK) profile.