A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure–activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75μM.

High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ∼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.

A flexible route to analogues of dihydroimidazo[5,1-a]isoquinolines is described. The synthesis hinges on a sequential Ugi coupling, followed by a Bischler–Napieralski reaction to form the imidazole isoquinoline core. This route facilitates the introduction of a range of substitutions throughout the carbon framework.

The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.

A series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlorophenyl)methyl]-4-hydroxypiperidine analogs has been identified as nociceptin receptor ligands. These compounds display high affinity and functional activity at the nociceptin receptor. The synthesis and structure-activity relationships at the C-4 phenyl and N-1 positions are described and the antitussive activity of a selected compound is reported.

A series of 4-hydroxy-4-phenylpiperidines have been synthesized and bind to the nociceptin receptor with high affinity. The synthesis and structure-activity relationships at the N-1 and C-4 are described.

La presente invention concerne l'utilisation des agonistes du recepteur ORL-1 pour le traitement de la toux ; seuls ou en combinaison avec un ou plusieurs agents pour le traitement de la toux, des symptomes allergiques et asthmatiques. L'invention concerne plus particulierement l'utilisation des agonistes du recepteur ORL-1 representes dans la formule (I) ou un sel pharmaceutiquement acceptable ou une combinaison, dans laquelle: la ligne en pointilles represente une double liaison optionnelle ; X1 represente eventuellement un alkyle, cycloalkyle, aryle, heteroaryle ou heterocycloalkyle substitue; X2 represente -CHO, -CN, eventuellement un amino, alkyle, ou aryle substitue; ou X1 represente eventuellement un heterocyclyle benzocondense substitue et X2 represente un hydrogene; ou X1 et X2 forment ensemble un groupe heterocyclyle spiro benzocondense R?1, R2, R3 et R4? sont independamment l'un de l'autre H et alkyle, ou (R?1 et R4) ou (R2 et R3) ou (R1 et R3) ou (R2 et R4?) ensemble peuvent former un pont alkylene compose de 1 a 3 atomes de carbone ; Z1 est eventuellement un alkyle, aryle, heteroaryle, cycloalkyle ou heterocycloalkyle substitue,ou -CO?2?(alkyl ou amino substitue) ou CN; Z?2? represente H ou Z1; Z3 represente H ou alkyle; ou Z?1, R2 et Z3?, forment ensemble, avec le carbone auquel ils sont attaches, des anneaux insatures ou satures a cycle double.