Phthalazinone-based lactams and cyclic ureas as ROCK2 selective inhibitors

Zilun Hu; Doree Sitkoff; Peter W Glunz; Yan Zou; Cailan Wang; Jodi K Muckelbauer; Leonard P Adam; Ruth R Wexler; Mimi L Quan

doi:10.1016/j.bmcl.2023.129304

Phthalazinone-based lactams and cyclic ureas as ROCK2 selective inhibitors

Bioorg Med Chem Lett. 2023 May 15:88:129304. doi: 10.1016/j.bmcl.2023.129304. Epub 2023 Apr 28.

Authors

Zilun Hu¹, Doree Sitkoff², Peter W Glunz², Yan Zou², Cailan Wang², Jodi K Muckelbauer², Leonard P Adam², Ruth R Wexler², Mimi L Quan²

Affiliations

¹ Research & Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, NJ 08543-5400, USA. Electronic address: zilun.hu@bms.com.
² Research & Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, NJ 08543-5400, USA.

PMID: 37119973
DOI: 10.1016/j.bmcl.2023.129304

Abstract

Derivatives of lactam, cyclic urea and carbamate were explored as aniline amide replacements in a series of phthalazinone-based ROCK inhibitors. Potent ROCK2 inhibitors such as 22 were identified with excellent overall kinase selectivity as well as good isoform selectivity over ROCK1.

Keywords: Lactam; Phthalazinone; ROCK2 selective inhibitor; Rho kinase; X-ray crystal structure.

MeSH terms

Amides*
Lactams* / pharmacology
Protein Isoforms
rho-Associated Kinases* / antagonists & inhibitors

Substances

Amides
Lactams
Protein Isoforms
rho-Associated Kinases