title: Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives.
abstract: A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than rosiglitazone and pioglitazone. PMT13 showed better PPARgamma transactivation than the standard compounds. Pharmacokinetic study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show any treatment-related adverse effects.
authors.affiliation: Discovery Chemistry, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India. madhavangr@drreddys.com
authors.forename: Gurram R
authors.initials: GR
authors.lastname: Madhavan
authors.forename: Ranjan
authors.initials: R
authors.lastname: Chakrabarti
authors.forename: Reeba K
authors.initials: RK
authors.lastname: Vikramadithyan
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: V
authors.initials: V
authors.lastname: Balraju
authors.forename: B M
authors.initials: BM
authors.lastname: Rajesh
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
authors.forename: Sunil K B
authors.initials: SK
authors.lastname: Kumar
authors.forename: Braj B
authors.initials: BB
authors.lastname: Lohray
authors.forename: Vidya B
authors.initials: VB
authors.lastname: Lohray
authors.forename: Ramanujam
authors.initials: R
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D051379:Mice; D008820:Mice, Obese; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011744:Pyrimidinones; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; C089946:2,4-thiazolidinedione