Inhibition of ALK2 with bicyclic pyridyllactams.

Autor: Witten MR; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States. Electronic address: mwitten@incyte.com., Wu L; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States., Lai CT; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States., Kapilashrami K; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States., Pusey M; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States., Gallagher K; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States., Chen Y; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States., Yao W; Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Jan 01; Vol. 55, pp. 128452. Date of Electronic Publication: 2021 Nov 13.
DOI: 10.1016/j.bmcl.2021.128452
Abstrakt: Activin receptor-like kinase 2 (ALK2) has been implicated as a key target in multiple rare diseases. Herein, we describe the design of a novel bicyclic lactam series of potent and selective ALK2 inhibitors. This manuscript details an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor. Furthermore, we provide a detailed strategy for progressing this project in the future.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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