William P. Feeney

Human β3-adrenergic receptor agonists containing 1,2,3-triazole-substituted benzenesulfonamides

Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.

L-770,644 : A potent and selective human β3 adrenergic receptor agonist with improved oral bioavailability

L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical evaluation.

Human β3 andrenergic receptor agonists containing imidazolidinone and imidazolone benzenesulfonamides

The cyclopentylpropylimidazolidinone L-766,892 is a potent beta3 AR agonist (EC50 5.7 nM, 64% activation) with 420- and 130-fold selectivity over binding to the beta1 and beta2 ARs, respectively. In anesthetized rhesus monkeys, L-766,892 elicited dose-dependent hyperglycerolemia (ED50 0.1 mg/kg) with minimal effects on heart rate.

3-pyridylethanolamines: Potent and selective human β3 adrenergic receptor agonists

The 3-pyridylethanolamine L-757,793 is a potent beta 3 AR agonist (EC50 6.3 nM, 70% activation) with 1,300- and 500-fold selectivity over binding to the beta 1 and beta 2 ARs, respectively. L-757,793 stimulated lipolysis in rhesus monkeys (ED50 0.2 mg/kg) with a maximum response equivalent to that elicited by isoproterenol.

Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core.

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.

Human β3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides

Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.

Discovery of an orally bioavailable alkyl oxadiazole β3 adrenergic receptor agonist

5-n-Pentyl oxadiazole substituted benzenesulfonamide 8 is a potent and selective beta3 adrenergic receptor agonist (beta3 EC50 = 23 nM, beta1 IC50 = 3000 nM, beta2 IC50 = 3000 nM). The compound has high oral bioavailability in dogs (62%) and rats (36%) and is among the most orally bioavailable beta3 adrenergic receptor agonists reported to date.

Potent, selective 3-pyridylethanolamine β3 adrenergic receptor agonists possessing a thiazole benzenesulfonamide pharmacophore

A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective beta3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.

Substituted oxazole benzenesulfonamides as potent human β3 adrenergic receptor agonists

As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.

Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study.

Tissue distribution, bioavailability, and efficacy of alendronate in preventing progression of resorption of teeth were evaluated in cats. [Butyl-4-14C-]-alendronate accumulates on subgingival tooth and alveolar bone surfaces adjacent to vascularized tissue resulting in concentration of the drug around tooth roots. Three cats were treated with a 0.03 mg/kg IV bolus of [butyl-4-14C-]-alendronate followed by blood, urine, and feces collection and euthanasia 24-hours later. Drug tissue distribution was accessed by autoradiography and sample combustion. To assess bioavailability, 12 cats were administered alendronate orally (3.0 or 9.0 mg/kg in water or 9.0 mg/kg in tuna water) and urine was collected for 24-hours. In these formulations, alendronate oral bioavailability in cats was approximately 3 %. In addition, 10 cats with radiographic evidence of pre-existing tooth resorption (14 affected teeth) were treated with vehicle or 3.0 mg/kg alendronate per os once weekly for 22-weeks and, then, 9.0 mg/kg per os twice weekly for 27-weeks in a random, masked study. Radiographic area of resorption was measured and progression scored every 3 to 4-months. In placebo-treated cats, resorption progressed in five of six teeth (+ 97 % average increase in area of resorption), whereas progression of resorption was seen in only three of eight affected teeth in alendronate-treated cats with a – 22 % average change (decrease) in area (P < 0.01 difference in number of teeth showing progression; P < 0.001 difference in area of resorption). Alendronate accumulated preferentially on subgingival tooth surfaces and adjacent alveolar bone and, at a dose of 9 mg/kg twice weekly, effectively slowed or arrested the progression of resorption.