Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors
Deng, X; Shen, J; Zhu, H; Xiao, J; Sun, R; Xie, F; Lam, C; Wang, J; Qiao, Y; Tavallaie, MS; Hu, Y; Du, Y; Li, J; Fu, L; Jiang, F
The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors. © 2018 Elsevier Ltd
Anti-diabetic; DPP-4 inhibitor; Molecular docking; Pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives; Structure-based drug design; 2 [(5 chloro 7 oxopyrazolo(1,5 a)pyrimidin 4(7h) yl)methyl]benzonitrile; 2 [[5 (3 aminopiperidin 1 yl) 7 oxopyrazolo(1,5 a) pyrimidin 4(7h) yl]methyl]benzonitrile; 2 [[7 (3 aminopiperidin 1 yl) 5 chloropyrazolo(1,5 a) pyrimidin 6 yl]methyl] benzonitrile; 2 [[7 oxo 5 (piperazin 1 yl)pyrazolo(1,5 a)pyrimidin 4(7h) yl]methyl]benzonitrile; 4 (2 nitrobenzyl) 5 (piperazin 1 yl)pyrazolo[1,5 a]pyrimidin 7(4h) one; 4 (4 methylbenzyl) 5 (piperazin 1 yl)pyrazolo[1,5 a] pyrimidin 7(4h) one; 4 (4 nitrobenzyl) 5 (piperazin 1 yl)pyrazolo[1,5 a]pyrimidin 7 (4h) one; 4 benzyl 5 (piperazin 1 yl)pyrazolo[1,5 a]pyrimidin 7(4h) one; 4 benzyl 5 chloropyrazolo[1,5 a]pyrimidin 7(4h) one; 4 [(5 chloro 7 oxopyrazolo(1,5 a)pyrimidin 4(7h) yl)methyl]benzonitrile; 4 [[5 (3 aminopiperidin 1 yl) 7 oxopyrazolo(1,5 a) pyrimidin 4(7h) yl]methyl]benzoic acid; 5 (3 aminopiperidin 1 yl) 4 (2 fluorobenzyl)pyrazolo (1,5 a)pyrimidin 7(4h) one; 5 (3 aminopiperidin 1 yl) 4 (4 methylbenzyl)pyrazolo [1,5 a]pyrimidin 7(4h) one; 5 (3 aminopiperidin 1 yl) 4 (4 nitrobenzyl)pyrazolo[1,5 a] pyrimidin 7(4h) one; 5 chloro 4 (2 fluorobenzyl)pyrazolo[1,5 a]pyrimidin 7(4h) one; 5 chloro 4 (2 nitrobenzyl)pyrazolo[1,5 a]pyrimidin 7(4h) one; 5 chloro 4 (4 methylbenzyl)pyrazolo[1,5 a]pyrimidin 7(4h) one; 5 chloro 4 (4 nitrobenzyl)pyrazolo[1,5 a]pyrimidin 7(4h) one; 5(3 aminopiperidin 1 yl) 4 benzylpyrazolo[1,5 a] pyrimidin 7(4h) one; dipeptidyl peptidase IV inhibitor; ethyl 4 [(5 chloro 7 oxopyrazolo(1,5 a)pyrimidin 4(7h) yl)methyl]benzoate; ethyl 4 [[5 (3 aminopiperidin 1 yl) 7 oxopyrazolo(1,5 a) pyrimidin 4(7h) yl]methyl]benzoate; ethyl 4 [[5 [3 [(tert butoxycarbonyl)amino]piperidin 1 yl]7 oxopyrazolo(1,5 a)pyrimidin 4(7h) yl]methyl]benzoate; pyrazolo[1,5 a]pyrimidin 7(4h) one core; tert butyl [1 [4 (2 cyanobenzyl) 7 oxo 4,7 dihydropyrazolo(1,5 a)pyrimidin 5 yl]piperidin 3 yl]carbamate; tert butyl [1 [4 (2 fluorobenzyl) 7 oxo 4,7 dihydropyrazolo(1,5 a)pyrimidin 5 yl]piperidin 3 yl]carbamate; tert butyl [1 [4 (4 methylbenzyl) 7 oxo 4,7 dihydropyrazolo(1,5 a)pyrimidin 5 yl]piperidin 3 yl]carbamate; tert butyl [1 [4 (4-nitrobenzyl) 7 oxo 4,7 dihydropyrazolo (1,5 a)pyrimidin 5 yl]piperidin 3 yl]carbamate; tert butyl [1 [4 benzyl 7 oxo 4,7 dihydropyrazolo(1,5 a)pyrimidin 5 yl]piperidin 3 yl]carbamate; unclassified drug; unindexed drug; antidiabetic agent; dipeptidyl peptidase IV; dipeptidyl peptidase IV inhibitor; pyrazole derivative; pyrazolo(1,5-a)pyrimidin-7(4H)-one; pyrimidinone derivative; animal experiment; animal model; Article; cell selection; cell viability; cellular parameters; controlled study; cytotoxicity; diabetes mellitus; drug design; drug selectivity; drug structure; drug synthesis; glucose tolerance test; IC50; in vitro study; in vivo study; male; molecular docking; mouse; non insulin dependent diabetes mellitus; nonhuman; process optimization; animal; binding site; C57BL mouse; cell survival; chemically induced; chemistry; drug design; drug effect; enzyme active site; experimental diabetes mellitus; Hep-G2 cell line; human; metabolism; pathology; structure activity relation; Animals; Binding Sites; Catalytic Domain; Cell Survival; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Glucose Tolerance Test; Hep G2 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Pyrazoles; Pyrimidinones; Structure-Activity Relationship