Document Report Card

ID: ALA1149119

Journal: J Med Chem

Title: Discovery of a potent and novel motilin agonist.

Authors: Li JJ, Chao HG, Wang H, Tino JA, Lawrence RM, Ewing WR, Ma Z, Yan M, Slusarchyk D, Seethala R, Sun H, Li D, Burford NT, Stoffel RH, Salyan ME, Li CY, Witkus M, Zhao N, Rich A, Gordon DA.

Abstract: A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.

CiteXplore: 15027861

DOI: 10.1021/jm0304865