Chromenones as potent bradykinin B1 antagonists

Marian C Bryan; Kaustav Biswas; Tanya A N Peterkin; Robert M Rzasa; Leyla Arik; Sonya G Lehto; Hong Sun; Feng-Yin Hsieh; Cen Xu; Robert T Fremeau; Jennifer R Allen

doi:10.1016/j.bmcl.2011.10.068

Chromenones as potent bradykinin B1 antagonists

Bioorg Med Chem Lett. 2012 Jan 1;22(1):619-22. doi: 10.1016/j.bmcl.2011.10.068. Epub 2011 Oct 28.

Authors

Marian C Bryan¹, Kaustav Biswas, Tanya A N Peterkin, Robert M Rzasa, Leyla Arik, Sonya G Lehto, Hong Sun, Feng-Yin Hsieh, Cen Xu, Robert T Fremeau, Jennifer R Allen

Affiliation

¹ Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

PMID: 22088753
DOI: 10.1016/j.bmcl.2011.10.068

Abstract

A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain.

MeSH terms

Animals
Benzopyrans / chemical synthesis*
Benzopyrans / pharmacology
Bradykinin B1 Receptor Antagonists*
Carrageenan / pharmacology
Chemistry, Pharmaceutical / methods
Chronic Pain / drug therapy
Drug Design
Humans
Hyperalgesia / drug therapy
Inhibitory Concentration 50
Kinetics
Models, Chemical
Rabbits
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

5-chlorochromenone
Benzopyrans
Bradykinin B1 Receptor Antagonists
Tumor Necrosis Factor-alpha
Carrageenan