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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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| Authors: | Stephen M Lynch Javier DeVicente Johannes C Hermann Saul Jaime-Figueroa Sue Jin Andreas Kuglstatter Hongju Li Allen Lovey John Menke Linghao Niu Vaishali Patel Douglas Roy Michael Soth Sandra Steiner Parcharee Tivitmahaisoon Minh Diem Vu Calvin Yee |
| Institution: | 1. Discovery Chemistry, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, United States;2. Inflammation Biology, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, United States;3. Discovery Technologies, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, United States |
| Abstract: | 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. |
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