Kirby MS

References (14)

Title : Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as potent and stable dipeptidyl peptidase IV inhibitors - Zhao_2013_Bioorg.Med.Chem.Lett_23_1622
Author(s) : Zhao G , Kwon C , Wang A , Robertson JG , Marcinkeviciene J , Parker RA , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :1622 , 2013
Abstract : Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.
ESTHER : Zhao_2013_Bioorg.Med.Chem.Lett_23_1622
PubMedSearch : Zhao_2013_Bioorg.Med.Chem.Lett_23_1622
PubMedID: 23416006

Title : DPP8 and DPP9 expression in cynomolgus monkey and Sprague Dawley rat tissues - Harstad_2013_Regul.Pept_186C_26
Author(s) : Harstad EB , Rosenblum JS , Gorrell MD , Achanzar WE , Minimo L , Wu J , Rosini-Marthaler L , Gullo R , Ordway ND , Kirby MS , Chadwick KD , Cosma GN , Moyer CF
Ref : Regul Pept , 186C :26 , 2013
Abstract : Dipeptidyl peptidases (DPPs) are proteolytic enzymes that regulate many physiological systems by degrading signaling peptides. DPP8 and DPP9 are distinct from DPP4 in sequence, cellular localization and expression levels, thus implying distinct functions. However, DPP8 and DPP9 expression needs further delineation. We evaluated DPP4, DPP8 and DPP9 expression using three independent methods at the mRNA, protein, and functional levels to better understand the local physiological contribution of each enzyme. Sprague Dawley rats and cynomolgus monkeys were selected for DPP4, DPP8 and DPP9 expression profiling to represent animal species commonly utilized for drug preclinical safety evaluation. A novel Xhibit assay of DPP protease activity was applied in addition to newly available antibodies for immunohistochemical localization. This combined approach can facilitate a functional evaluation of protease expression, which is important for understanding physiological relevance. Few inter-species differences were observed. Tissue mRNA and protein levels generally correlated to functional DPP4 and DPP8/9 enzymatic activity. All three proteins were seen in epithelial cells, lymphoid cells and some endothelial and vascular smooth muscle cells. Combined DPP8/DPP9 enzymatic activity was uniformly intracellular across tissues at approximately 10-fold lower levels than non-renal DPP4. Consistent levels of each DPP were detected among most non-renal tissues in rats and monkeys. DPP4 was ubiquitous, principally detected on cell membranes of epithelial and endothelial cells and was greatest in the kidney. The expression patterns suggest that DPP8 and DPP9 may act similarly across tissues, and that their actions might in part overlap with DPP4.
ESTHER : Harstad_2013_Regul.Pept_186C_26
PubMedSearch : Harstad_2013_Regul.Pept_186C_26
PubMedID: 23850796
Gene_locus related to this paper: rat-dpp9

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 : Potency, selectivity and prolonged binding of saxagliptin to DPP4: maintenance of DPP4 inhibition by saxagliptin in vitro and ex vivo when compared to a rapidly-dissociating DPP4 inhibitor - Wang_2012_BMC.Pharmacol_12_2
Author(s) : Wang A , Dorso C , Kopcho L , Locke G , Langish R , Harstad E , Shipkova P , Marcinkeviciene J , Hamann L , Kirby MS
Ref : BMC Pharmacol , 12 :2 , 2012
Abstract : BACKGROUND: Dipeptidylpeptidase 4 (DPP4) inhibitors have clinical benefit in patients with type 2 diabetes mellitus by increasing levels of glucose-lowering incretin hormones, such as glucagon-like peptide -1 (GLP-1), a peptide with a short half life that is secreted for approximately 1 hour following a meal. Since drugs with prolonged binding to their target have been shown to maximize pharmacodynamic effects while minimizing drug levels, we developed a time-dependent inhibitor that has a half-life for dissociation from DPP4 close to the duration of the first phase of GLP-1 release. RESULTS: Saxagliptin and its active metabolite (5-hydroxysaxagliptin) are potent inhibitors of human DPP4 with prolonged dissociation from its active site (Ki = 1.3 nM and 2.6 nM, t1/2 = 50 and 23 minutes respectively at 37 degrees C). In comparison, both vildagliptin (3.5 minutes) and sitagliptin ( < 2 minutes) rapidly dissociated from DPP4 at 37 degrees C. Saxagliptin and 5-hydroxysaxagliptin are selective for inhibition of DPP4 versus other DPP family members and a large panel of other proteases, and have similar potency and efficacy across multiple species.Inhibition of plasma DPP activity is used as a biomarker in animal models and clinical trials. However, most DPP4 inhibitors are competitive with substrate and rapidly dissociate from DPP4; therefore, the type of substrate, volume of addition and final concentration of substrate in these assays can change measured inhibition. We show that unlike a rapidly dissociating DPP4 inhibitor, inhibition of plasma DPP activity by saxagliptin and 5-hydroxysaxagliptin in an ex vivo assay was not dependent on substrate concentration when substrate was added rapidly because saxagliptin and 5-hydroxysaxagliptin dissociate slowly from DPP4, once bound. We also show that substrate concentration was important for rapidly dissociating DPP4 inhibitors. CONCLUSIONS: Saxagliptin and its active metabolite are potent, selective inhibitors of DPP4, with prolonged dissociation from its active site. They also demonstrate prolonged inhibition of plasma DPP4 ex vivo in animal models, which implies that saxagliptin and 5-hydroxysaxagliptin would continue to inhibit DPP4 during rapid increases in substrates in vivo.
ESTHER : Wang_2012_BMC.Pharmacol_12_2
PubMedSearch : Wang_2012_BMC.Pharmacol_12_2
PubMedID: 22475049

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 : Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors - O'Connor_2010_Bioorg.Med.Chem.Lett_20_6273
Author(s) : O'Connor SP , Wang Y , Simpkins LM , Brigance RP , Meng W , Wang A , Kirby MS , Weigelt CA , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :6273 , 2010
Abstract : The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.
ESTHER : O'Connor_2010_Bioorg.Med.Chem.Lett_20_6273
PubMedSearch : O'Connor_2010_Bioorg.Med.Chem.Lett_20_6273
PubMedID: 20833042

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

Title : Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation - Metzler_2008_Protein.Sci_17_240
Author(s) : Metzler WJ , Yanchunas J , Weigelt C , Kish K , Klei HE , Xie D , Zhang Y , Corbett M , Tamura JK , He B , Hamann LG , Kirby MS , Marcinkeviciene J
Ref : Protein Science , 17 :240 , 2008
Abstract : The inhibition of DPP-IV by saxagliptin has been proposed to occur through formation of a covalent but reversible complex. To evaluate further the mechanism of inhibition, we determined the X-ray crystal structure of the DPP-IV:saxagliptin complex. This structure reveals covalent attachment between S630 and the inhibitor nitrile carbon (C-O distance <1.3 A). To investigate whether this serine addition is assisted by the catalytic His-Asp dyad, we generated two mutants of DPP-IV, S630A and H740Q, and assayed them for ability to bind inhibitor. DPP-IV H740Q bound saxagliptin with an approximately 1000-fold reduction in affinity relative to DPP-IV WT, while DPP-IV S630A showed no evidence for binding inhibitor. An analog of saxagliptin lacking the nitrile group showed unchanged binding properties to the both mutant proteins, highlighting the essential role S630 and H740 play in covalent bond formation between S630 and saxagliptin. Further supporting mechanism-based inhibition by saxagliptin, NMR spectra of enzyme-saxagliptin complexes revealed the presence of three downfield resonances with low fractionation factors characteristic of short and strong hydrogen bonds (SSHB). Comparison of the NMR spectra of various wild-type and mutant DPP-IV:ligand complexes enabled assignment of a resonance at approximately 14 ppm to H740. Two additional DPP-IV mutants, Y547F and Y547Q, generated to probe potential stabilization of the enzyme-inhibitor complex by this residue, did not show any differences in inhibitor binding either by ITC or NMR. Together with the previously published enzymatic data, the structural and binding data presented here strongly support a histidine-assisted covalent bond formation between S630 hydroxyl oxygen and the nitrile group of saxagliptin.
ESTHER : Metzler_2008_Protein.Sci_17_240
PubMedSearch : Metzler_2008_Protein.Sci_17_240
PubMedID: 18227430
Gene_locus related to this paper: human-DPP4

Title : Potent non-nitrile dipeptidic dipeptidyl peptidase IV inhibitors - Simpkins_2007_Bioorg.Med.Chem.Lett_17_6476
Author(s) : Simpkins LM , Bolton S , Pi Z , Sutton JC , Kwon C , Zhao G , Magnin DR , Augeri DJ , Gungor T , Rotella DP , Sun Z , Liu Y , Slusarchyk WS , Marcinkeviciene J , Robertson JG , Wang A , Robl JA , Atwal KS , Zahler RL , Parker RA , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :6476 , 2007
Abstract : The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
ESTHER : Simpkins_2007_Bioorg.Med.Chem.Lett_17_6476
PubMedSearch : Simpkins_2007_Bioorg.Med.Chem.Lett_17_6476
PubMedID: 17937986

Title : Seco-prolinenitrile inhibitors of dipeptidyl peptidase IV define minimal pharmacophore requirements at P1 - Magnin_2006_Bioorg.Med.Chem.Lett_16_1731
Author(s) : Magnin DR , Taunk PC , Robertson JG , Wang A , Marcinkeviciene J , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :1731 , 2006
Abstract : A series of seco-prolinenitrile-containing dipeptides were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV, a promising new target for treatment of type 2 diabetes. The inhibitors described herein assess the minimum structural requirements at P1 for this enzyme, resulting in the identification of inhibitors with low nM potency.
ESTHER : Magnin_2006_Bioorg.Med.Chem.Lett_16_1731
PubMedSearch : Magnin_2006_Bioorg.Med.Chem.Lett_16_1731
PubMedID: 16376077

Title : Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Augeri_2005_J.Med.Chem_48_5025
Author(s) : Augeri DJ , Robl JA , Betebenner DA , Magnin DR , Khanna A , Robertson JG , Wang A , Simpkins LM , Taunk P , Huang Q , Han SP , Abboa-Offei B , Cap M , Xin L , Tao L , Tozzo E , Welzel GE , Egan DM , Marcinkeviciene J , Chang SY , Biller SA , Kirby MS , Parker RA , Hamann LG
Ref : Journal of Medicinal Chemistry , 48 :5025 , 2005
Abstract : Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
ESTHER : Augeri_2005_J.Med.Chem_48_5025
PubMedSearch : Augeri_2005_J.Med.Chem_48_5025
PubMedID: 16033281

Title : Probing prime substrate binding sites of human dipeptidyl peptidase-IV using competitive substrate approach - Kopcho_2005_Arch.Biochem.Biophys_436_367
Author(s) : Kopcho LM , Kim YB , Wang A , Liu MA , Kirby MS , Marcinkeviciene J
Ref : Archives of Biochemistry & Biophysics , 436 :367 , 2005
Abstract : Dipeptidyl peptidase-IV is a cell surface protease which plays an important role in glucose homeostasis through proteolytic inactivation of incretin hormones, primarily glucagon like peptide-1 (GLP-1). Substrate N-terminal amino acid (S2-S1) specificity is rather clearly defined, while no substantial information is available on the significance of amino acid interactions towards the C-terminus after the scissile bond (so called prime S1'-S4' or distant S5'-S28' sites). In the present study the increasing length of the peptide towards prime sites (S1'-S4') resulted in approximately 7-fold decrease in Km. Moreover, the Km for GLP-1 cleavage was comparable to that of an S2-S4' peptide, suggesting that few, if any, important enzyme-substrate interactions occur beyond the active site. Effect of substrate length on kcat was less obvious, but kcat/Km showed an increasing trend when His-Ala-pNA (representing the natural two N-terminal residues) was compared to GLP-1. To probe the impact of increasing substrate length on the free energy of activation (as has been suggested for elastase and chymotrypsin) we performed temperature studies. To adequately interpret thermodynamic data we sought to understand what steps limit the kcat expression. Steady-state parameters of the reactions catalyzed by serine proteases are composed of microscopic constants describing binding, acylation, and deacylation steps. Viscosity and pre-steady-state studies suggested that His-Ala-pNA cleavage is limited in the deacylation half-reaction, most likely the product release step. Thus, the free energy of activation, as calculated from the Eyring equation, is underestimated (at least for His-Ala-pNA) and the effect of substrate length on the acylation step (and transition-state stabilization) could not be unambiguously assessed.
ESTHER : Kopcho_2005_Arch.Biochem.Biophys_436_367
PubMedSearch : Kopcho_2005_Arch.Biochem.Biophys_436_367
PubMedID: 15797249

Title : Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors - Zhao_2005_Bioorg.Med.Chem.Lett_15_3992
Author(s) : Zhao G , Taunk PC , Magnin DR , Simpkins LM , Robl JA , Wang A , Robertson JG , Marcinkeviciene J , Sitkoff DF , Parker RA , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 15 :3992 , 2005
Abstract : Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
ESTHER : Zhao_2005_Bioorg.Med.Chem.Lett_15_3992
PubMedSearch : Zhao_2005_Bioorg.Med.Chem.Lett_15_3992
PubMedID: 16046120