Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva

Hirofumi Yamamoto; Naoki Sakai; Satoshi Ohte; Tomohiro Sato; Katsuhiko Sekimata; Takehisa Matsumoto; Kana Nakamura; Hisami Watanabe; Chiemi Mishima-Tsumagari; Akiko Tanaka; Yoshinobu Hashizume; Teruki Honma; Takenobu Katagiri; Kohei Miyazono; Hiroshi Tomoda; Mikako Shirouzu; Hiroo Koyama

doi:10.1016/j.bmcl.2021.127858

Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva

Bioorg Med Chem Lett. 2021 Apr 15:38:127858. doi: 10.1016/j.bmcl.2021.127858. Epub 2021 Feb 18.

Authors

Hirofumi Yamamoto¹, Naoki Sakai², Satoshi Ohte³, Tomohiro Sato⁴, Katsuhiko Sekimata⁵, Takehisa Matsumoto², Kana Nakamura², Hisami Watanabe², Chiemi Mishima-Tsumagari², Akiko Tanaka², Yoshinobu Hashizume⁶, Teruki Honma⁴, Takenobu Katagiri⁷, Kohei Miyazono⁸, Hiroshi Tomoda³, Mikako Shirouzu², Hiroo Koyama¹

Affiliations

¹ Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
² Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
³ Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁴ Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
⁵ Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: katsuhiko.sekimata@riken.jp.
⁶ RIKEN Program for Drug Discovery and Medical Technology Platforms, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁷ Division of Biomedical Sciences, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
⁸ Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

PMID: 33609658
DOI: 10.1016/j.bmcl.2021.127858

Abstract

Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.

Keywords: Activin receptor-like kinase-2 (ALK2); Bicyclic pyrazole derivatives; Fibrodysplasia ossificans progressiva (FOP).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type I / antagonists & inhibitors*
Activin Receptors, Type I / genetics
Activin Receptors, Type I / metabolism
Animals
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Humans
Mice
Molecular Structure
Mutation
Myositis Ossificans / drug therapy*
Myositis Ossificans / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Bridged Bicyclo Compounds, Heterocyclic
Protein Kinase Inhibitors
Pyrazoles
ACVR1 protein, human
Activin Receptors, Type I