Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists

Paul Gillespie; Robert A Goodnow Jr; Goutam Saha; Gopal Bose; Kakali Moulik; Catherine Zwingelstein; Michael Myers; Karin Conde-Knape; Sherrie Pietranico-Cole; Sung-Sau So

doi:10.1016/j.bmcl.2013.12.063

Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists

Bioorg Med Chem Lett. 2014 Feb 1;24(3):949-53. doi: 10.1016/j.bmcl.2013.12.063. Epub 2013 Dec 24.

Affiliations

¹ Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Electronic address: [email protected].
² Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
³ TCG Lifesciences Limited, Salt Lake Electronic Complex, Block BN, Plot 7, Sector V, Kolkata 700 091, India.
⁴ Metabolic and Vascular Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.

PMID: 24412066
DOI: 10.1016/j.bmcl.2013.12.063

Abstract

We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Keywords: Agonist; GPCR; GPR119; Oral glucose tolerance test; Type 2 diabetes.

MeSH terms

Animals
Drug Discovery*
Humans
Mice
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Gpr119 protein, mouse
Pyrazoles
Pyrimidines
Receptors, G-Protein-Coupled
pyrimidine