Substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones as hypoglycemic agents.
A series of dihydrobenzofuran and dihydrobenzopyran thiazolidine-2,4-diones (compounds 3-26) was synthesized from the corresponding aryl aldehydes 1 in two steps. These compounds represent conformationally restricted analogues of the novel hypoglycemic ciglitazone. The series was evaluated by hypoglycemic effects in vitro by measuring stimulation of 2-deoxyglucose uptake in L6 myocytes and stimulation of expression of the glucose transporter protein in 3T3-L1 adipocytes. In vivo hypoglycemic effects were evaluated in the genetically obese ob/ob mouse, and structure-activity relationships are discussed. On the basis of this in vivo potency, we have selected the 2(R)-benzylbenzopyran derivative to be further studied in a clinical setting.
Clark
D A
DA
Pfizer, Inc., Groton, Connecticut 06340.
Goldstein
S W
SW
Volkmann
R A
RA
Eggler
J F
JF
Holland
G F
GF
Hulin
B
B
Stevenson
R W
RW
Kreutter
D K
DK
Gibbs
E M
EM
Krupp
M N
MN
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D001572:Benzofurans; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D009004:Monosaccharide Transport Proteins; D013844:Thiazoles; D003847:Deoxyglucose