Reduction in glucose levels in STZ diabetic rats by 4-(2,2-dimethyl-1-oxopropyl)benzoic acid: a prodrug approach for targeting the liver.
The overproduction of glucose by the liver in NIDDM patients markedly contributes to their fasting hyperglycemia and is a direct consequence of the increased oxidation of excess free fatty acids (FFA) being released from the adipocyte. 2-(1,1-Dimethylethyl)-2-(4-methylphenyl)[1,3]dioxolane (SAH51-641, 1) has previously been demonstrated to reduce glucose levels in animal models of diabetes by reducing fatty acid oxidation and hence depriving the system of the energy and cofactors necessary for gluconeogenesis. However, attempts at lowering glucose levels in vivo with 1 have been associated with toxicity in other organs such as the testes. An approach was developed utilizing the natural processing of triglyceride-like intermediates as a basis for selectively targeting the absorption, processing, and delivery of a prodrug to the liver. Compounds were identified by this method which lowered glucose levels in vivo without releasing toxic amounts of the active metabolites of 1 into circulation.
Bebernitz
G R
GR
Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, USA. greg.bernitz@pharma.novartis.com
Dain
J G
JG
Deems
R O
RO
Otero
D A
DA
Simpson
W R
WR
Strohschein
R J
RJ
D000818:Animals; D019540:Area Under Curve; D001565:Benzoates / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C421622:4-(2,2-dimethyl-1--oxopropyl)benzoic acid 1,2,4-butanetriyl ester; C116991:4-(2,2-dimethyl-1-oxopropyl)benzoic acid; D001565:Benzoates; D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D011355:Prodrugs