Discovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists.

Optimization of the lead 2a led to the identification of a novel diarylketoxime class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Our focus was directed toward improvement of hERG activity and metabolic stability. The representative derivative 4b showed potent and dose-dependent body weight reduction in diet-induced obese (DIO) C57BL/6J mice after oral administration. The synthesis and structure-activity relationships of the novel diarylketoxime MCH-1R antagonists are described.

Design, synthesis and evaluation of a novel cyclohexanamine class of neuropeptide Y Y1 receptor antagonists.

A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K(+) channel and serotonin transporter.

Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity.

The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.

Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists.

The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.

2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists.

The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.

Design, synthesis, and structure-activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine.

Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.

A novel class of cycloalkano[b]pyridines as potent and orally active opioid receptor-like 1 antagonists with minimal binding affinity to the hERG K+ channel.

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.