Jay M. Matthews

Synthesis and biological evaluation of novel indoloazepine derivatives as non-peptide vasopressin V2 receptor antagonists.

A series of novel 3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indoles was synthesized and tested for vasopressin receptor antagonist activity. We identified compounds with high affinity for the human V2 receptor and good selectivity over the human V1a receptor. Compound 6c bound to V2 receptors with an IC(50) value of 20 nM, had >100-fold selectivity over V1a receptors, and inhibited cAMP formation in a cellular V2 functional assay with an IC(50) value of 70 nM.

Improvement of dyslipidemia, insulin sensitivity, and energy balance by a peroxisome proliferator–activated receptor α agonist

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.

Characterization of RWJ-351647, a novel nonpeptide vasopressin V2 receptor antagonist.

1 Antagonists of the V2 vasopressin (AVP) receptor are aquaretic agents, inhibiting water resorption without stimulating electrolyte excretion. In this set of experiments, a novel V2 receptor antagonist, RWJ‐351647, was characterized in vitro and in vivo. 2 RWJ‐351647 displaced 3H‐AVP binding from cloned human V2 and V1A receptors with Ki values of 1 nmol/L and 24 nmol/L. In assays using transfected HEK293 cells expressing either human or rat V2 receptors, RWJ‐351647 inhibited AVP‐induced cAMP accumulation with Ki values of 3 nmol/L and 6 nmol/L, respectively. 3 RWJ‐351647 was very selective in binding assays and showed only weak functional antagonist activity at either the cloned human V1B and oxytocin receptors or the human platelet V1A receptor. No agonist activity was seen with the compound at any receptor. 4 Pharmacokinetic studies in rats showed RWJ‐351647 to be 41.9% bioavailable after a single oral administration. After repeated daily dosing over 5 days, the oral bioavailability remained at 43.9% with no change in the compound peak plasma levels or clearance rate. 5 In efficacy studies, RWJ‐351647 increased urine output and decreased urine osmolality with oral doses as low as 0.1 mg/kg and 1.0 mg/kg in rats and cynomolgus monkeys, respectively. In a multiple dose study in primates, RWJ‐351647 maintained a consistent aquaretic effect over 10 days without increasing sodium or potassium excretion. 6 In summary, RWJ‐351647 was shown to be a selective and potent V2 receptor antagonist with sustainable aquaretic activity in both rats and primates. The preclinical data suggest that RWJ‐351647 is a potent and effective aquaretic agent with potential for use in diseases characterized by water retention.