Harrity T

References (4)

Title : Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]py ridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778) - Devasthale_2013_J.Med.Chem_56_7343
Author(s) : Devasthale P , Wang Y , Wang W , Fevig J , Feng J , Wang A , Harrity T , Egan D , Morgan N , Cap M , Fura A , Klei HE , Kish K , Weigelt C , Sun L , Levesque P , Moulin F , Li YX , Zahler R , Kirby MS , Hamann LG
Ref : Journal of Medicinal Chemistry , 56 :7343 , 2013
Abstract : Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
ESTHER : Devasthale_2013_J.Med.Chem_56_7343
PubMedSearch : Devasthale_2013_J.Med.Chem_56_7343
PubMedID: 23964740
Gene_locus related to this paper: human-DPP4

Title : 7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site - Wang_2011_Bioorg.Med.Chem.Lett_21_6646
Author(s) : Wang W , Devasthale P , Wang A , Harrity T , Egan D , Morgan N , Cap M , Fura A , Klei HE , Kish K , Weigelt C , Sun L , Levesque P , Li YX , Zahler R , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :6646 , 2011
Abstract : Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 muM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 mumol/kg in ob/ob mice.
ESTHER : Wang_2011_Bioorg.Med.Chem.Lett_21_6646
PubMedSearch : Wang_2011_Bioorg.Med.Chem.Lett_21_6646
PubMedID: 21996520
Gene_locus related to this paper: human-DPP4

Title : Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes - Brigance_2010_Bioorg.Med.Chem.Lett_20_4395
Author(s) : Brigance RP , Meng W , Fura A , Harrity T , Wang A , Zahler R , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :4395 , 2010
Abstract : Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
ESTHER : Brigance_2010_Bioorg.Med.Chem.Lett_20_4395
PubMedSearch : Brigance_2010_Bioorg.Med.Chem.Lett_20_4395
PubMedID: 20598534

Title : Discovery of 6-(Aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxa mides as Potent, Selective Dipeptidyl Peptidase-4 (DPP4) Inhibitors - Meng_2010_J.Med.Chem_53_5620
Author(s) : Meng W , Brigance RP , Chao HJ , Fura A , Harrity T , Marcinkeviciene J , O'Connor SP , Tamura JK , Xie D , Zhang Y , Klei HE , Kish K , Weigelt CA , Turdi H , Wang A , Zahler R , Kirby MS , Hamann LG
Ref : Journal of Medicinal Chemistry , 53 :5620 , 2010
Abstract : Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
ESTHER : Meng_2010_J.Med.Chem_53_5620
PubMedSearch : Meng_2010_J.Med.Chem_53_5620
PubMedID: 20684603
Gene_locus related to this paper: human-DPP4