Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1. Issue 10 (15th May 2020)

• Record Type: Journal Article
• Authors: Fensome, Andrew; Ambler, Catherine M.; Arnold, Eric; Banker, Mary Ellen; Clark, James D.; Dowty, Martin E.; Efremov, Ivan V.; Flick, Andrew; Gerstenberger, Brian S.; Gifford, Roger S.; Gopalsamy, Ariamala; Hegen, Martin; Jussif, Jason; Limburg, David C.; Lin, Tsung H.; Pierce, Betsy S.; Sharma, Raman; Trujillo, John I.; Vajdos, Felix F.; Vincent, Fabien; Wan, Zhao-Kui; Xing, Li; Yang, Xiaojing; Yang, Xin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 10(2020)
• Publication Date: 2020-05-15
• Subjects: TYK2 -- JAK1 -- Kinase -- Autoimmune -- Inflammation -- Psoriasis -- Arthritis; 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.2020.115481
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.