Inhibition of ALK2 with bicyclic pyridyllactams

Michael R Witten; Liangxing Wu; Cheng-Tsung Lai; Kanishk Kapilashrami; Michelle Pusey; Karen Gallagher; Yaoyu Chen; Wenqing Yao

doi:10.1016/j.bmcl.2021.128452

Inhibition of ALK2 with bicyclic pyridyllactams

Bioorg Med Chem Lett. 2022 Jan 1:55:128452. doi: 10.1016/j.bmcl.2021.128452. Epub 2021 Nov 13.

Authors

Michael R Witten¹, Liangxing Wu², Cheng-Tsung Lai², Kanishk Kapilashrami², Michelle Pusey², Karen Gallagher², Yaoyu Chen², Wenqing Yao²

Affiliations

¹ Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States. Electronic address: mwitten@incyte.com.
² Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States.

PMID: 34780900
DOI: 10.1016/j.bmcl.2021.128452

Abstract

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.

Keywords: 2-Aminopyridines; ACVR1; ALK2; Inhibitors; Lactams.

MeSH terms

Activin Receptors, Type I / antagonists & inhibitors*
Activin Receptors, Type I / metabolism
Dose-Response Relationship, Drug
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
beta-Lactams / chemical synthesis
beta-Lactams / chemistry
beta-Lactams / pharmacology*

Substances

Protein Kinase Inhibitors
beta-Lactams
ACVR1 protein, human
Activin Receptors, Type I