Biomedical subjects
Publications and source records attributed to Graham S Poindexter.
A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC(50) of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.
4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1 receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones.
Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).
beta-Alanine derivative 2 (IC(50)=16 nM) and related compounds were found to be potent MC4R agonists.
Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).
The dihydropyridine is currently one of the lead compounds in the neuropeptide-Y(1) (NPY-Y(1)) receptor antagonist program. Compound is a selective, high affinity ligand at the NPY-Y(1) receptors (IC(50)=4.2 nM) in SK-N-MC cells. To further expand the SAR study surrounding this dihydropyridine core structure we succeeded in synthesizing an analogous series of dihydropyrazine derivatives. This structural modification yielded compounds substantially different from the parent molecules in terms of molecular polarization and electron distribution while the overall molecular structure was generally preserved. This altered property should therefore provide us with additional SAR information on the optimal binding requirement with NPY receptors.
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