Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS

Peripherally Selective Diphenyl Purine Antagonist of the CB1 Receptor

Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl purine CB1 antagonist otenabant <b>1</b>. Compound <b>9</b> (<i>N</i>-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9<i>H</i>-purin-6-yl]­piperidin-4-yl}­pentanamide) is a potent, orally absorbed antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of Δ⁹-tetrahydrocannabinol through the CB1 receptor

Identification of Neuropeptide S Antagonists: Structure–Activity Relationship Studies, X‑ray Crystallography, and in Vivo Evaluation

Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1<i>H</i>-oxazolo­[3,4-α]­pyrazin-3­(5<i>H</i>)-ones were synthesized and evaluated for antagonist activity at the neuropeptide S receptor. The absolute configuration was determined by chiral resolution of the key synthetic intermediate, followed by analysis of one of the individual enantiomers by X-ray crystallography. The <i>R</i> isomer was then converted to a biologically active compound (<b>34</b>) that had a <i>K</i>_e of 36 nM. The most potent compound displayed enhanced aqueous solubility compared with the prototypical antagonist SHA-68 and demonstrated favorable pharmacokinetic properties for behavioral assessment. In vivo analysis in mice indicated a significant blockade of NPS induced locomotor activity at an ip dose of 50 mg/kg. This suggests that analogs having improved drug-like properties will facilitate more detailed studies of the neuropeptide S receptor system

TableS10-PropertiesandEstimates-2017-12-11

Estimated TK properties (e.g., Volume of Distribution, Fraction bioavailable) for in vivo rat studies

TableS9-InVivoData-2017-12-11

Plasma concentration vs. time toxicokinetic data collected for a variety of chemicals in Sprague-Dawley rat

TableS11-TKSummaryStats-2017-12-11

Model TK statistics (Cmax, AUC) for in vivo rat studies