| Autor: |
Hansen BB, Jepsen TH, Larsen M, Sindet R, Vifian T, Burhardt MN, Larsen J, Seitzberg JG, Carnerup MA, Jerre A, Mølck C, Lovato P, Rai S; Medicinal Chemistry, GVK Biosciences Private Limited, 28 A, IDA Nacharam, Hyderabad 500076, India., Nasipireddy VR; Medicinal Chemistry, GVK Biosciences Private Limited, 28 A, IDA Nacharam, Hyderabad 500076, India., Ritzén A |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2020 Jul 09; Vol. 63 (13), pp. 7008-7032. Date of Electronic Publication: 2020 Jun 08. |
| DOI: |
10.1021/acs.jmedchem.0c00359 |
| Abstrakt: |
Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40 , which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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