Eiermann GJ

References (14)

Title : A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice - Berger_2018_Endocrinol.Diabetes.Metab_1_e00002
Author(s) : Berger JP , SinhaRoy R , Pocai A , Kelly TM , Scapin G , Gao YD , Pryor KAD , Wu JK , Eiermann GJ , Xu SS , Zhang X , Tatosian DA , Weber AE , Thornberry NA , Carr RD
Ref : Endocrinol Diabetes Metab , 1 :e00002 , 2018
Abstract : Aims: Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity. Methods: We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy. Results: Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice. Conclusion: The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.
ESTHER : Berger_2018_Endocrinol.Diabetes.Metab_1_e00002
PubMedSearch : Berger_2018_Endocrinol.Diabetes.Metab_1_e00002
PubMedID: 30815539
Gene_locus related to this paper: human-DPP4

Title : Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes - Mu_2009_Eur.J.Pharmacol_623_148
Author(s) : Mu J , Petrov A , Eiermann GJ , Woods J , Zhou YP , Li Z , Zycband E , Feng Y , Zhu L , Roy RS , Howard AD , Li C , Thornberry NA , Zhang BB
Ref : European Journal of Pharmacology , 623 :148 , 2009
Abstract : Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control in patients with type 2 diabetes by prolonging and potentiating the actions of incretin hormones. This study is designed to determine the effects of the DPP-4 inhibitor sitagliptin on improving islet function in a mouse model of insulin resistance and insulin secretion defects. ICR mice were pre-treated with high fat diet and a low dose of streptozotocin to induce insulin resistance and impaired insulin secretion, respectively. Diabetic mice were treated with sitagliptin or the sulfonylurea agent glipizide as admixture to high fat diet for ten weeks. Sustained reduction of blood glucose, HbA(1c), circulating glucagon and improvement in oral glucose tolerance were observed in mice treated with sitagliptin. In contrast, glipizide improved glycemic control only during the early weeks and to a lesser degree compared to sitagliptin, and had no effect on circulating glucagon levels or glucose tolerance. The improvement in glycemic control in sitagliptin-treated mice was associated with a significant increase in glucose-dependent insulin secretion in both perfused pancreas and isolated islets. Importantly, in contrast to the lack of effect by glipizide, sitagliptin significantly restored beta and alpha cell mass as well as alpha/beta cell ratio. These data indicate that DPP-4 inhibition by sitagliptin provided better overall improvement of glycemic control compared to glipizide in the high fat diet/streptozotocin induced diabetic mouse model. The ability of sitagliptin to enhance islet cell function may offer insight into the potential for disease modification.
ESTHER : Mu_2009_Eur.J.Pharmacol_623_148
PubMedSearch : Mu_2009_Eur.J.Pharmacol_623_148
PubMedID: 19765579

Title : Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors - Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
Author(s) : Edmondson SD , Mastracchio A , Cox JM , Eiermann GJ , He H , Lyons KA , Patel RA , Patel SB , Petrov A , Scapin G , Wu JK , Xu S , Zhu B , Thornberry NA , Roy RS , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :4097 , 2009
Abstract : A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
ESTHER : Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
PubMedSearch : Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
PubMedID: 19539471
Gene_locus related to this paper: human-DPP4

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 : 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV - Duffy_2007_Bioorg.Med.Chem.Lett_17_2879
Author(s) : Duffy JL , Kirk BA , Wang L , Eiermann GJ , He H , Leiting B , Lyons KA , Patel RA , Patel SB , Petrov A , Scapin G , Wu JK , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2879 , 2007
Abstract : A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
ESTHER : Duffy_2007_Bioorg.Med.Chem.Lett_17_2879
PubMedSearch : Duffy_2007_Bioorg.Med.Chem.Lett_17_2879
PubMedID: 17350841
Gene_locus related to this paper: human-DPP4

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 : 4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV - Kaelin_2007_Bioorg.Med.Chem.Lett_17_5806
Author(s) : Kaelin DE , Smenton AL , Eiermann GJ , He H , Leiting B , Lyons KA , Patel RA , Patel SB , Petrov A , Scapin G , Wu JK , Thornberry NA , Weber AE , Duffy JL
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :5806 , 2007
Abstract : A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
ESTHER : Kaelin_2007_Bioorg.Med.Chem.Lett_17_5806
PubMedSearch : Kaelin_2007_Bioorg.Med.Chem.Lett_17_5806
PubMedID: 17851076
Gene_locus related to this paper: human-DPP4

Title : (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]tr iazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Edmondson_2006_J.Med.Chem_49_3614
Author(s) : Edmondson SD , Mastracchio A , Mathvink RJ , He J , Harper B , Park YJ , Beconi M , Di Salvo J , Eiermann GJ , He H , Leiting B , Leone JF , Levorse DA , Lyons K , Patel RA , Patel SB , Petrov A , Scapin G , Shang J , Roy RS , Smith A , Wu JK , Xu S , Zhu B , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 49 :3614 , 2006
Abstract : A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]tr iazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
ESTHER : Edmondson_2006_J.Med.Chem_49_3614
PubMedSearch : Edmondson_2006_J.Med.Chem_49_3614
PubMedID: 16759103
Gene_locus related to this paper: human-DPP4

Title : Discovery of potent, selective, and orally bioavailable oxadiazole-based dipeptidyl peptidase IV inhibitors - Xu_2006_Bioorg.Med.Chem.Lett_16_5373
Author(s) : Xu J , Wei L , Mathvink RJ , Edmondson SD , Eiermann GJ , He H , Leone JF , Leiting B , Lyons KA , Marsilio F , Patel RA , Patel SB , Petrov A , Scapin G , Wu JK , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :5373 , 2006
Abstract : A novel series of oxadiazole based amides have been shown to be potent DPP-4 inhibitors. The optimized compound 43 exhibited excellent selectivity over a variety of DPP-4 homologs.
ESTHER : Xu_2006_Bioorg.Med.Chem.Lett_16_5373
PubMedSearch : Xu_2006_Bioorg.Med.Chem.Lett_16_5373
PubMedID: 16919457
Gene_locus related to this paper: human-DPP4

Title : Discovery of potent, selective, and orally bioavailable pyridone-based dipeptidyl peptidase-4 inhibitors - Xu_2006_Bioorg.Med.Chem.Lett_16_1346
Author(s) : Xu J , Wei L , Mathvink R , Edmondson SD , Mastracchio A , Eiermann GJ , He H , Leone JF , Leiting B , Lyons KA , Marsilio F , Patel RA , Petrov A , Wu JK , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :1346 , 2006
Abstract : anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species.
ESTHER : Xu_2006_Bioorg.Med.Chem.Lett_16_1346
PubMedSearch : Xu_2006_Bioorg.Med.Chem.Lett_16_1346
PubMedID: 16332437

Title : Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9 - Lankas_2005_Diabetes_54_2988
Author(s) : Lankas GR , Leiting B , Roy RS , Eiermann GJ , Beconi MG , Biftu T , Chan CC , Edmondson S , Feeney WP , He H , Ippolito DE , Kim D , Lyons KA , Ok HO , Patel RA , Petrov AN , Pryor KA , Qian X , Reigle L , Woods A , Wu JK , Zaller D , Zhang X , Zhu L , Weber AE , Thornberry NA
Ref : Diabetes , 54 :2988 , 2005
Abstract : Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.
ESTHER : Lankas_2005_Diabetes_54_2988
PubMedSearch : Lankas_2005_Diabetes_54_2988
PubMedID: 16186403

Title : (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Kim_2005_J.Med.Chem_48_141
Author(s) : Kim D , Wang L , Beconi M , Eiermann GJ , Fisher MH , He H , Hickey GJ , Kowalchick JE , Leiting B , Lyons K , Marsilio F , McCann ME , Patel RA , Petrov A , Scapin G , Patel SB , Roy RS , Wu JK , Wyvratt MJ , Zhang BB , Zhu L , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 48 :141 , 2005
Abstract : A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
ESTHER : Kim_2005_J.Med.Chem_48_141
PubMedSearch : Kim_2005_J.Med.Chem_48_141
PubMedID: 15634008
Gene_locus related to this paper: human-DPP4

Title : Discovery of potent and selective orally bioavailable beta-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors - Edmondson_2005_Bioorg.Med.Chem.Lett_15_3048
Author(s) : Edmondson SD , Mastracchio A , Duffy JL , Eiermann GJ , He H , Ita I , Leiting B , Leone JF , Lyons KA , Makarewicz AM , Patel RA , Petrov A , Wu JK , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 15 :3048 , 2005
Abstract : anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.
ESTHER : Edmondson_2005_Bioorg.Med.Chem.Lett_15_3048
PubMedSearch : Edmondson_2005_Bioorg.Med.Chem.Lett_15_3048
PubMedID: 15908206