Discovery of novel pyrrole derivatives as potent agonists for the niacin receptor GPR109A

Yuriko Miyazawa; Takahiro Yamaguchi; Mitsuhiro Yamaguchi; Keiko Tago; Akihiro Tamura; Daisuke Sugiyama; Takahide Aburatani; Tomohiro Nishizawa; Nobuya Kurikawa; Keita Kono

doi:10.1016/j.bmcl.2020.127105

Discovery of novel pyrrole derivatives as potent agonists for the niacin receptor GPR109A

Bioorg Med Chem Lett. 2020 May 15;30(10):127105. doi: 10.1016/j.bmcl.2020.127105. Epub 2020 Mar 10.

Authors

Affiliations

¹ External Affairs Department, Daiichi Sankyo Co., Ltd., Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan. Electronic address: [email protected].
² Modality Research Laboratories, Daiichi Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
³ R&D Planning & Management Department, Daiichi Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁴ Medicinal Chemistry Research Laboratories, Daiichi Sankyo RD Novare Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁵ Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd., Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
⁶ Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁷ External Affairs Department, Daiichi Sankyo Co., Ltd., Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan.
⁸ Specialty Medicine Research Laboratories II, Daiichi Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁹ Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 32199732
DOI: 10.1016/j.bmcl.2020.127105

Abstract

Novel pyrrole derivatives were discovered as potent agonists of the niacin receptor, GPR109A. During the derivatization, compound 16 was found to be effective both in vitro and in vivo. The compound 16 exhibited a significant reduction of the non-esterified fatty acid in human GPR109A transgenic rats, and the duration of its in vivo efficacy was much longer than niacin.

Keywords: GPR109A; Lipolysis; Niacin; Non-esterified fatty acid; Pyrrole.

MeSH terms

Animals
Drug Design
Fatty Acids, Nonesterified / metabolism
Humans
Lipolysis / drug effects
Nicotinic Agonists / chemistry*
Nicotinic Agonists / metabolism
Nicotinic Agonists / pharmacology
Pyrroles / chemistry*
Pyrroles / metabolism
Pyrroles / pharmacology
Rats
Rats, Transgenic
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism
Structure-Activity Relationship

Substances

Fatty Acids, Nonesterified
HCAR2 protein, human
Nicotinic Agonists
Pyrroles
Receptors, G-Protein-Coupled