Discovery of benzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivatives as orally available bromodomain and extra-terminal domain (BET) inhibitors with efficacy in an in vivo psoriatic animal model

Masanori Sato; Takekazu Kondo; Yasushi Kohno; Shigeki Seto

doi:10.1016/j.bmc.2021.116015

Discovery of benzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivatives as orally available bromodomain and extra-terminal domain (BET) inhibitors with efficacy in an in vivo psoriatic animal model

Bioorg Med Chem. 2021 Mar 15:34:116015. doi: 10.1016/j.bmc.2021.116015. Epub 2021 Jan 25.

Authors

Masanori Sato¹, Takekazu Kondo¹, Yasushi Kohno¹, Shigeki Seto²

Affiliations

¹ Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
² Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: shigeki.seto@mb.kyorin-pharm.co.jp.

PMID: 33549905
DOI: 10.1016/j.bmc.2021.116015

Abstract

Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.

Keywords: BRD4 inhibitor; Benzo[f]pyrido[4,3-b][1,4]oxazepin-10-one; Psoriasis.

MeSH terms

Animals
Dose-Response Relationship, Drug
Gene Expression Regulation / drug effects
Mice
Models, Molecular
Molecular Structure
Nerve Tissue Proteins / antagonists & inhibitors*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Nuclear Proteins / classification
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oxazepines / administration & dosage
Oxazepines / chemical synthesis
Oxazepines / chemistry*
Oxazepines / pharmacology*
Receptors, Cell Surface / antagonists & inhibitors*
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism
Structure-Activity Relationship
Transcription Factors / classification
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Brd4 protein, mouse
Dner protein, mouse
Nerve Tissue Proteins
Nuclear Proteins
Oxazepines
Receptors, Cell Surface
Transcription Factors