Pyrazole antagonists of the CB1 receptor with reduced brain penetration

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• 作者：Alan Fulp ; Yanan Zhang ; Katherine Bortoff ; Herbert Seltzman ; Rodney Snyder ; Robert Wiethe ; George Amato ; Rangan Maitra ; ^{rmaitra@rti.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BBB ; blood&ndash ; brain barrier ; BOP ; benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate ; CB ; cannabinoid receptors ; CB1 ; cannabinoid receptor 1 ; CB2 ; cannabinoid receptor 2 ; CHO-K1 ; Chinese hamster ovary cells ; CMA 80 ; 80% chloroform ; 18% methanol ; and 2% ammonium hydroxide ; CNS ; central nervous system ; Ke ; apparent affinity constant ; MDCK-mdr1 ; Madin&ndash ; Darby canine kidney cells transfected with the human MDR1 gene ; IP3 ; inositol phosphatase 3 ; MRM ; multiple reaction mon
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：24
• 期：5
• 页码：1063-1070
• 全文大小：841 K

文摘

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.