Stewart K

References (2)

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

Title : Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors - Pei_2006_J.Med.Chem_49_3520
Author(s) : Pei Z , Li X , Longenecker K , von Geldern TW , Wiedeman PE , Lubben TH , Zinker BA , Stewart K , Ballaron SJ , Stashko MA , Mika AK , Beno DW , Long M , Wells H , Kempf-Grote AJ , Madar DJ , McDermott TS , Bhagavatula L , Fickes MG , Pireh D , Solomon LR , Lake MR , Edalji R , Fry EH , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 49 :3520 , 2006
Abstract : A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
ESTHER : Pei_2006_J.Med.Chem_49_3520
PubMedSearch : Pei_2006_J.Med.Chem_49_3520
PubMedID: 16759095
Gene_locus related to this paper: human-DPP4