Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries

Allyn T Londregan; David W Piotrowski; Kentaro Futatsugi; Joseph S Warmus; Markus Boehm; Philip A Carpino; Janice E Chin; Ann M Janssen; Nicole S Roush; Joanne Buxton; Terri Hinchey

doi:10.1016/j.bmcl.2012.12.076

Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1407-11. doi: 10.1016/j.bmcl.2012.12.076. Epub 2013 Jan 5.

Authors

Allyn T Londregan¹, David W Piotrowski, Kentaro Futatsugi, Joseph S Warmus, Markus Boehm, Philip A Carpino, Janice E Chin, Ann M Janssen, Nicole S Roush, Joanne Buxton, Terri Hinchey

Affiliation

¹ Pfizer Worldwide Research & Development, Eastern Point Road, Groton, CT 06340, United States. [email protected]

PMID: 23337601
DOI: 10.1016/j.bmcl.2012.12.076

Abstract

Optimization of a high-throughput screening hit led to the discovery of a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. This novel chemotype was rapidly developed through iterative combinatorial library synthesis. It was determined that in vitro agonist potency correlated with functional activity data from human peripheral blood monocytes.

MeSH terms

Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology*
Combinatorial Chemistry Techniques
Humans
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Amides
GPBAR1 protein, human
Pyrazoles
Receptors, G-Protein-Coupled
pyrazole