ABSTRACT
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dogs , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.
Subject(s)
Adenosine Deaminase Inhibitors , Amides/chemical synthesis , Glycoproteins/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Amides/pharmacology , Animals , Azetidines , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4 , Disease Models, Animal , Fluorine , Glucose Tolerance Test , Inhibitory Concentration 50 , Mice , Pyrrolidines/pharmacology , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described glycogen phosphorylase inhibitors that reduce glycogenolysis in cells and lower plasma glucose in ob/ob mice (J. Med. Chem., 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, up to 90% reduction in plasma cholesterol was noted after 2 week treatment. Cholesterol reductions were also noted in ob/ob mice and in rats. In HepG2 cells, CP-320626 acutely and dose-dependently inhibited cholesterolgenesis without affecting fatty acid synthesis. Inhibition occurred together with a dose-dependent increase in the cholesterol precursor, lanosterol, suggesting that cholesterolgenesis inhibition was due to lanosterol 14alpha-demethylase (CYP51) inhibition. In ob/ob mice, acute treatment with CP-320626 resulted in a decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. CP-320626 and analogs directly inhibited rhCYP51, and this inhibition was highly correlated with HepG2 cell cholesterolgenesis inhibition (R2 = 0.77). These observations indicate that CP-320626 inhibits cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. Dual-action glycogenolysis and cholesterolgenesis inhibitors therefore have the potential to favorably affect both the hyperglycemia and the dyslipidemia of type 2 diabetes.
Subject(s)
Amides/pharmacology , Anticholesteremic Agents/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Hypoglycemic Agents/pharmacology , Indoles/pharmacology , Oxidoreductases/antagonists & inhibitors , Amides/blood , Amides/chemical synthesis , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Cholesterol/biosynthesis , Cytochrome P-450 Enzyme System/metabolism , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Indoles/blood , Indoles/chemical synthesis , Lanosterol/blood , Liver/drug effects , Liver/enzymology , Mice , Mice, Inbred C57BL , Mice, Obese , Oxidoreductases/metabolism , Rats , Rats, Sprague-Dawley , Sterol 14-Demethylase , Structure-Activity RelationshipABSTRACT
1,5-Cyclooctadiene can be stereoselectively transformed into a substituted bicyclo[3.3.0]octane ring system under palladium catalysis with concomitant formation of three carbon-carbon bonds. Reaction with an aryl iodide or triflate and malonate gives an exo-endo product, while the reaction with a malonate in the presence of oxygen affords a bis-endo adduct.