title: Pyrazole antagonists of the CB1 receptor with reduced brain penetration.
abstract: Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant.
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Fulp
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bortoff
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Seltzman
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: Rodney
authors.initials: R
authors.lastname: Snyder
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wiethe
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA.
authors.forename: George
authors.initials: G
authors.lastname: Amato
authors.affiliation: Discovery Science and Technology, RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709-2194, USA. Electronic address: rmaitra@rti.org.
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant
chemical_list: C481395:4-aminopiperidine; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant
keywords: Antagonist; Blood brain barrier; CB1; CB2; Cannabinoid; MDCK; PAMPA; Peripheral; Pyrazole; Rimonabant
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