Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents.
We report here the synthesis of a series of 5-[4-[2-[substituted phthalazinones-2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3-benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and their plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in this series, showed better in vitro PPARgamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showed better plasma glucose and triglyceride lowering activity than the standard drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatment-related adverse effect.
Madhavan
G R
GR
Discovery Chemistry, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, 500 050, Hyderabad, India.
Chakrabarti
R
R
Kumar
S K
SK
Misra
P
P
Mamidi
R N
RN
Balraju
V
V
Kasiram
K
K
Babu
R K
RK
Suresh
J
J
Lohray
B B
BB
Lohrayb
V B
VB
Iqbal
J
J
Rajagopalan
R
R
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects*; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000097:blood; D000077288:Troglitazone
D001786:Blood Glucose; D002839:Chromans; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010078:Oxazines; D010793:Phthalazines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; C089946:2,4-thiazolidinedione; D000077288:Troglitazone; D000077205:Pioglitazone