Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome

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• 作者：Stephen M. Lynch^a ; ^{stephen.lynch@roche.com} ; Javier DeVicente^a ; Johannes C. Hermann^a ; Saul Jaime-Figueroa^a ; Sue Jin^b ; Andreas Kuglstatter^c ; Hongju Li^a ; Allen Lovey^a ; John Menke^b ; Linghao Niu^b ; Vaishali Patel^b ; Douglas Roy^a ; Michael Soth^a ; Sandra Steiner^a ; Parcharee Tivitmahaisoon^a ; Minh Diem Vu^b ; Calvin Yee^a
• 关键词：Kinase inhibitors ; Janus kinase ; JAK ; Structure based design ; Kinase selectivity ; Conformational bias
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 May, 2013
• 年：2013
• 卷：23
• 期：9
• 页码：2793-2800
• 全文大小：3146 K

文摘

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.