Design and synthesis of 1H-pyrazolo[3,4-c]pyridine derivatives as a novel structural class of potent GPR119 agonists

Daisuke Matsuda; Yohei Kobashi; Ayako Mikami; Madoka Kawamura; Fumiyasu Shiozawa; Kenichi Kawabe; Makoto Hamada; Koji Oda; Shinichi Nishimoto; Kayo Kimura; Masako Miyoshi; Noriko Takayama; Hiroyuki Kakinuma; Norikazu Ohtake

doi:10.1016/j.bmcl.2016.06.050

Design and synthesis of 1H-pyrazolo[3,4-c]pyridine derivatives as a novel structural class of potent GPR119 agonists

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3441-6. doi: 10.1016/j.bmcl.2016.06.050. Epub 2016 Jun 20.

Affiliations

¹ Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
² Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
³ Research Support, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.

PMID: 27390068
DOI: 10.1016/j.bmcl.2016.06.050

Abstract

Design and synthesis of a novel class of 1H-pyrazolo[3,4-c]pyridine GPR119 receptor agonists are described. Lead compound 4 was identified through the ligand-based drug design approach. Modification of the left-hand aryl group (R(1)) and right-hand piperidine N-capping group (R(2)) led to the identification of compound 24 as a single-digit nanomolar GPR119 agonist.

Keywords: G-protein coupled receptor; GPR119 agonist; Pyrazolopyridine; Type 2 diabetes mellitus.

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

GPR119 protein, human
Pyridines
Receptors, G-Protein-Coupled