Phenylacetic acid derivatives as hPPAR agonists.
Beginning with the weakly active lead structure 1, a new series of hPPAR agonists was developed. In vivo glucose and triglyceride lowering activity was obtained by homologation and oxamination to 3, then conversion to substituted benzisoxazoles 4 and 5. Further manipulation afforded benzofurans 6 and 7. Compound 7 was of comparable potency as a glucose and triglyceride lowering agent in insulin resistant rodents to BRL 49653.
Santini
Conrad
C
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. conrad_santini@merck.com
Berger
Gregory D
GD
Han
Wei
W
Mosley
Ralph
R
MacNaul
Karen
K
Berger
Joel
J
Doebber
Thomas
T
Wu
Margaret
M
Moller
David E
DE
Tolman
Richard L
RL
Sahoo
Soumya P
SP
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010648:Phenylacetates; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone