Backes_2007_Bioorg.Med.Chem.Lett_17_2005

Reference

Title : Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit - Backes_2007_Bioorg.Med.Chem.Lett_17_2005
Author(s) : Backes BJ , Longenecker K , Hamilton GL , Stewart K , Lai C , Kopecka H , von Geldern TW , Madar DJ , Pei Z , Lubben TH , Zinker BA , Tian Z , Ballaron SJ , Stashko MA , Mika AK , Beno DW , Kempf-Grote AJ , Black-Schaefer C , Sham HL , Trevillyan JM
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2005 , 2007
Abstract :

A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.

PubMedSearch : Backes_2007_Bioorg.Med.Chem.Lett_17_2005
PubMedID: 17276063
Gene_locus related to this paper: ratno-dpp4 , human-DPP4

Related information

Inhibitor AIL    DLI
Gene_locus AIL    DLI    ratno-dpp4    human-DPP4
Structure AIL    DLI    ratno-dpp4    human-DPP4    2OAE    2OAG

Citations formats

Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM (2007)
Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit
Bioorganic & Medicinal Chemistry Lett 17 :2005

Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM (2007)
Bioorganic & Medicinal Chemistry Lett 17 :2005