Kelly TM

References (2)

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 : Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes - Wu_2016_ACS.Med.Chem.Lett_7_498
Author(s) : Wu WL , Hao J , Domalski M , Burnett DA , Pissarnitski D , Zhao Z , Stamford A , Scapin G , Gao YD , Soriano A , Kelly TM , Yao Z , Powles MA , Chen S , Mei H , Hwa J
Ref : ACS Med Chem Lett , 7 :498 , 2016
Abstract : In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.
ESTHER : Wu_2016_ACS.Med.Chem.Lett_7_498
PubMedSearch : Wu_2016_ACS.Med.Chem.Lett_7_498
PubMedID: 27190600
Gene_locus related to this paper: human-DPP4