title: Synthesis and evaluation of thiouracil derivatives as dipeptidyl peptidase IV inhibitors.
abstract: A series of thiouracil derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study indicated the influence of substituted chemical modifications on thiouracil scaffold. Compounds 8 (IC(50) = 0.32 μM), 9 (IC(50) = 0.29 μM), and 12 (IC(50) = 0.25 μM) showed excellent dipeptidyl peptidase IV inhibition having heterocyclic substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors among all the compounds screened. Single dose (10 mg/kg) of the compounds 8, 9, and 12 significantly reduced glucose excursion during oral glucose tolerance test in streptozotocin-induced diabetic rat model. The present study on substituted thiouracil derivatives shows good-to-moderate inhibitory potential of dipeptidyl peptidase IV enzyme.
authors.affiliation: Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar, Sector-3, M B Road, New Delhi 110017, India. mani120484@gmail.com
authors.forename: Mani
authors.initials: M
authors.lastname: Sharma
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
authors.forename: Monica
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C586337:2-((2-(4-aminopiperidin-1-yl)-2-oxoethyl)sulfanyl)-4-hydroxy-6-phenylpyrimidine-5-carbonitrile; C586335:2-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethylsulfanyl)-4-hydroxy-6-phenyl-pyrimidine-5-carbonitrile; C586336:4-hydroxy-2-((2-oxo-2-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)sulfanyl)-6-phenylpyrimidine-5-carbonitrile; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010879:Piperazines; D010880:Piperidines; D011743:Pyrimidines; D013889:Thiouracil; D018819:Dipeptidyl Peptidase 4