Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 50 (9), 2200-12

Potent Nonpeptide Antagonists of the Bradykinin B1 Receptor: Structure-Activity Relationship Studies With Novel Diaminochroman Carboxamides

Affiliations

Potent Nonpeptide Antagonists of the Bradykinin B1 Receptor: Structure-Activity Relationship Studies With Novel Diaminochroman Carboxamides

Kaustav Biswas et al. J Med Chem.

Abstract

The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.

Similar articles

See all similar articles

Cited by 1 PubMed Central articles

  • Rank Order Entropy: Why One Metric Is Not Enough
    MR McLellan et al. J Chem Inf Model 51 (9), 2302-19. PMID 21875058.
    The use of Quantitative Structure-Activity Relationship models to address problems in drug discovery has a mixed history, generally resulting from the misapplication of Q …

MeSH terms

LinkOut - more resources

Feedback