Synthesis and evaluation of a series of 2,4-diaminopyridine derivatives as potential positron emission tomography tracers for neuropeptide Y Y1 receptors.

A series of 2,4-diaminopyridine derivatives was synthesized and evaluated as potential candidates for neuropeptide Y (NPY) Y1 receptor positron emission tomography (PET) tracers. Derivatives bearing substitutions allowing reliable access to radiolabeling were designed, focusing on Y1 binding affinity and lipophilicity. The advanced derivatives 2n and 2o were identified as promising PET tracer candidates.

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.

Identification of MK-1925: a selective, orally active and brain-penetrable opioid receptor-like 1 (ORL1) antagonist.

Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.

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.

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.

Identification of an orally active opioid receptor-like 1 (ORL1) receptor antagonist 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine as clinical candidate.

Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activity, excellent selectivity over other opioid receptors, and in vivo efficacy after oral dosing. Currently clinical trials of 10 are underway.

Involvement of organic anion transporting polypeptide 1a5 (Oatp1a5) in the intestinal absorption of endothelin receptor antagonist in rats.

PURPOSE: To assess the contribution of organic anion transporting polypeptide 1a5 (Oatp1a5/Oatp3) in the intestinal absorption of an orally active endothelin receptor antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylene-dioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (compound-A) in rats. METHODS: Uptakes of [(14)C]compound-A by Oatp1a5-expressing Xenopus laevis oocytes and isolated rat enterocytes were evaluated. RESULTS: The uptake of compound-A by Oatp1a5-expressing oocytes was significantly higher than that by water-injected oocytes and Oatp1a5-mediated uptake was saturable with K(m) value of 116 microM. Compound-A was taken up into isolated enterocytes in time- and concentration-dependent manners and the estimated K(m) value was 83 microM, which was close to that for the Oatpt1a5-mediated uptake in oocytes. Both uptakes of compound-A by Oatp1a5-expressing oocytes and enterocytes were pH-sensitive with significantly higher uptake at acidic pH than those at neutral pH. Uptakes of compound-A into Oatp1a5-expressing oocytes and enterocytes were significantly decreased in the presence of Oatp1a5 substrates such as bromosulfophthalein and taurocholic acid. CONCLUSIONS: These results consistently suggested that Oatp1a5 is contributing to the intestinal absorption of compound-A at least in part, and the transporter-mediated absorption seems to be maximized at the acidic microenvironment of epithelial cells in the small intestine in rats.

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.

Hepatobiliary transport of a nonpeptidic endothelin antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl) cyclopentenol[1,2-b]pyridine-6-carboxylic acid: uptake by isolated rat hepatocytes and canalicular membrane vesicles.

PURPOSE: Hepatobiliary excretions of drugs from the blood to the bile include two essential transmembrane processes: uptake into hepatocytes and secretion from hepatocytes. The purpose of this study was to clarify the transport mechanisms underlying these processes for a new non-peptide endothelin antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxy-phenyl)cyclopentenol[1,2-b]pyridine-6-carboxylic acid (J-104132). METHODS: Biliary excretion of J-104132 was assessed in rats after intravenous injection. To evaluate the hepatic uptake process, J-104132 was incubated with freshly isolated rat hepatocytes and the uptake of J-104132 was calculated. To evaluate the biliary secretion process, the uptake of J-104132 into rat canalicular membrane vesicles that were isolated from normal Sprague-Dawley rats or Eisai hyperbilirubinemic rats was measured. RESULTS: After intravenous injection, J-104132 was recovered from the bile quantitatively (99.7 +/- 1.3%) as its intact form. J-104132 was taken up by isolated rat hepatocytes in a time- and temperature-dependent manner. The uptake was saturable with Km and Vmax of 5.7 microM and 564 pmol/min/10(6) cells, respectively. The uptake was Na+ independent and was reduced in the presence of ATP depleters (rotenone and carbonyl cyanide-p-(trifluoromethoxy)-phenylhydrazone), organic anions (dibromosulfophthalein, indocyanine green, BQ-123, and pravastatin), and bile acids (taurecholate and cholate). In Sprague-Dawley rats, J-104132 was taken up by canalicular membrane vesicle ATP-dependently with Km and Vmax values of 6.1 microM and 552 pmol/min/mg protein, respectively. However, ATP-dependent uptake disappeared in Eisai hyperbilirubinemic rats. CONCLUSIONS: These data suggest that energy-dependent and carrier-mediated transport systems play important roles in hepatobiliary excretion of J-104132 (both uptake and secretion processes), which is the main excretion route in rats. As for the secretion process of J-104132, an involvement of mrp2 was demonstrated.