Hypoglycemic prodrugs of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid.
SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2, 2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2, 2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits medium-chain acyltransferase. 1-3 and 4-tert-butylbenzoic acid all cause testicular degeneration in rats at pharmacologically active doses. 14b (FOX 988) is a prodrug of 3, which is metabolized in the liver at a rate sufficient enough to have hypoglycemic potency (an ED50 of 65 micromol/kg, 28 mg/kg/day, for glucose lowering), yet by avoiding significant escape of the metabolite 3 to the systemic circulation, it avoids the testicular toxicity at doses up to 1500 micromol/kg/day. 14b was selected for clinical studies.
Aicher
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TD
Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, New Jersey 07901, USA.
Bebernitz
G R
GR
Bell
P A
PA
Brand
L J
LJ
Dain
J G
JG
Deems
R
R
Fillers
W S
WS
Foley
J E
JE
Knorr
D C
DC
Nadelson
J
J
Otero
D A
DA
Simpson
R
R
Strohschein
R J
RJ
Young
D A
DA
D000098:Acetophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005227:Fatty Acids / Q000378:metabolism; D005943:Gluconeogenesis; D007004:Hypoglycemic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects / Q000378:metabolism
C116992:4-(2,2-dimethyl-1-hydroxypropyl)benzoic acid; C116991:4-(2,2-dimethyl-1-oxopropyl)benzoic acid; D000098:Acetophenones; D001565:Benzoates; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D011355:Prodrugs; C094089:SDZ FOX 988