Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones.
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.
Reddy
K A
KA
Medicinal and Organic Chemistry, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India.
Lohray
B B
BB
Bhushan
V
V
Bajji
A C
AC
Reddy
K V
KV
Reddy
P R
PR
Krishna
T H
TH
Rao
I N
IN
Jajoo
H K
HK
Rao
N V
NV
Chakrabarti
R
R
Dileepkumar
T
T
Rajagopalan
R
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists; D014280:Triglycerides / Q000097:blood
C119475:5-(4-(N-(5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl)pyrrolidin-2-ylmethoxy)phenylene)thiazolidine-2,4-dione; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D011759:Pyrrolidines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; D014280:Triglycerides