Pryor KD

References (7)

Title : Expression, purification and crystallization of human prolylcarboxypeptidase. - Abeywickrema_2010_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_66_702
Author(s) : Abeywickrema PD , Patel SB , Byrne NJ , Diehl RE , Hall DL , Ford RE , Rickert KW , Reid JC , Shipman JM , Geissler WM , Pryor KD , SinhaRoy R , Soisson SM , Lumb KJ , Sharma S
Ref : Acta Crystallographica Sect F Struct Biol Cryst Commun , 66 :702 , 2010
Abstract : Prolylcarboxypeptidase (PrCP) is a lysosomal serine carboxypeptidase that cleaves a variety of C-terminal amino acids adjacent to proline and has been implicated in diseases such as hypertension and obesity. Here, the robust production, purification and crystallization of glycosylated human PrCP from stably transformed CHO cells is described. Purified PrCP yielded crystals belonging to space group R32, with unit-cell parameters a = b = 181.14, c = 240.13 A, that diffracted to better than 2.8 A resolution.
ESTHER : Abeywickrema_2010_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_66_702
PubMedSearch : Abeywickrema_2010_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_66_702
PubMedID: 20516604
Gene_locus related to this paper: human-PRCP

Title : Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity - Zhou_2010_J.Med.Chem_53_7251
Author(s) : Zhou C , Garcia-Calvo M , Pinto S , Lombardo M , Feng Z , Bender K , Pryor KD , Bhatt UR , Chabin RM , Geissler WM , Shen Z , Tong X , Zhang Z , Wong KK , Roy RS , Chapman KT , Yang L , Xiong Y
Ref : Journal of Medicinal Chemistry , 53 :7251 , 2010
Abstract : Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 microM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
ESTHER : Zhou_2010_J.Med.Chem_53_7251
PubMedSearch : Zhou_2010_J.Med.Chem_53_7251
PubMedID: 20857914
Gene_locus related to this paper: human-PRCP

Title : Peptidomic profiling of human cerebrospinal fluid identifies YPRPIHPA as a novel substrate for prolylcarboxypeptidase - Zhao_2010_Proteomics_10_2882
Author(s) : Zhao X , Southwick K , Cardasis HL , Du Y , Lassman ME , Xie D , El-Sherbeini M , Geissler WM , Pryor KD , Verras A , Garcia-Calvo M , Shen DM , Yates NA , Pinto S , Hendrickon RC
Ref : Proteomics , 10 :2882 , 2010
Abstract : Prolylcarboxypeptidase (PRCP) is a serine protease that catalyzes the cleavage of C-terminal amino acids linked to proline in peptides. It is ubiquitously expressed and is involved in regulating blood pressure, proliferation, inflammation, angiogenesis, and weight maintenance. To identify the candidate proximal target engagement markers for PRCP inhibition in the central nervous system, we profiled the peptidome of human cerebrospinal fluid to look for PRCP substrates using a MS-based in vitro substrate profiling assay. These experiments identified a single peptide, with the sequence YPRPIHPA, as a novel substrate for PRCP in human cerebrospinal fluid. The peptide YPRPIHPA is from the extracellular portion of human endothelin B receptor-like protein 2.
ESTHER : Zhao_2010_Proteomics_10_2882
PubMedSearch : Zhao_2010_Proteomics_10_2882
PubMedID: 20517885
Gene_locus related to this paper: human-PRCP

Title : Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing subsituted triazolopiperazines - Kim_2008_J.Med.Chem_51_589
Author(s) : Kim D , Kowalchick JE , Brockunier LL , Parmee ER , Eiermann GJ , Fisher MH , He H , Leiting B , Lyons K , Scapin G , Patel SB , Petrov A , Pryor KD , Roy RS , Wu JK , Zhang X , Wyvratt MJ , Zhang BB , Zhu L , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 51 :589 , 2008
Abstract : A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
ESTHER : Kim_2008_J.Med.Chem_51_589
PubMedSearch : Kim_2008_J.Med.Chem_51_589
PubMedID: 18201067

Title : Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate) - Kim_2007_Bioorg.Med.Chem.Lett_17_3373
Author(s) : Kim D , Kowalchick JE , Edmondson SD , Mastracchio A , Xu J , Eiermann GJ , Leiting B , Wu JK , Pryor KD , Patel RA , He H , Lyons KA , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :3373 , 2007
Abstract : A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
ESTHER : Kim_2007_Bioorg.Med.Chem.Lett_17_3373
PubMedSearch : Kim_2007_Bioorg.Med.Chem.Lett_17_3373
PubMedID: 17434732

Title : Design, synthesis, and biological evaluation of triazolopiperazine-based beta-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors - Kowalchick_2007_Bioorg.Med.Chem.Lett_17_5934
Author(s) : Kowalchick JE , Leiting B , Pryor KD , Marsilio F , Wu JK , He H , Lyons KA , Eiermann GJ , Petrov A , Scapin G , Patel RA , Thornberry NA , Weber AE , Kim D
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :5934 , 2007
Abstract : Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
ESTHER : Kowalchick_2007_Bioorg.Med.Chem.Lett_17_5934
PubMedSearch : Kowalchick_2007_Bioorg.Med.Chem.Lett_17_5934
PubMedID: 17827003
Gene_locus related to this paper: human-DPP4

Title : Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs - Faidley_2006_Exp.Biol.Med.(Maywood)_231_1373
Author(s) : Faidley TD , Leiting B , Pryor KD , Lyons K , Hickey GJ , Thompson DR
Ref : Exp Biol Med (Maywood) , 231 :1373 , 2006
Abstract : The enzyme dipeptidyl peptidase-IV (DPP-IV) inactivates a variety of bioactive peptides, including glucagon-like peptide-1 (GLP-1) and growth hormone releasing hormone (GHRH). Inhibiting DPP-IV in order to increase circulating GLP-1 is of interest as a treatment for Type II diabetes. Inactivation of DPP-IV may also increase circulating GHRH, potentially enhancing growth in domestic animals. To test the hypothesis that inhibition of DPP-IV activity will influence the growth hormone/ IGF-1 axis, growing pigs (Sus scrofa domesticus, 78 kg) were treated with a DPP-IV inhibitor (Compound 1, the 2,5-difluor-ophenyl analog of the triazolopiperazine MK0431, sitagliptin), and plasma concentrations of IGF-1 were monitored. Pigs were administered either sterile saline (0.11 ml/kg followed by a continuous infusion at 2 ml/hr for 72 hrs, controls, n = 2), Compound 1 (2.78 mg/kg followed by a continuous infusion at 0.327 mg/kg x hr for 72 hrs, n = 4) or GHRH (0.11 ml/kg sterile saline, followed by a continuous infusion of GHRH at 2.5 microg/ kg x hr for 48 hrs, n = 4). Plasma concentrations of Compound 1 were maintained at 1 microM, which resulted in a 90% inhibition of circulating DPP-IV activity. Relative to the predose 24-hr period, area under the IGF-1 concentration curve (AUC) tended to be lower (P = 0.062) with Compound 1 (.79 +/- 130 ng/ml x hr) than controls (543 +/- 330 ng/ml x hr). GHRH treatment increased the IGF-1 AUC (1210 +/- 160 ng/ml x hr, P = 0.049 vs. controls and P = 0.001 vs. Compound 1). We conclude that inhibition of DPP-IV does not alter the circulating levels of IGF-1 in the growing pig.
ESTHER : Faidley_2006_Exp.Biol.Med.(Maywood)_231_1373
PubMedSearch : Faidley_2006_Exp.Biol.Med.(Maywood)_231_1373
PubMedID: 16946406