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Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

ABSTRACT: Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (1) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (2) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 1 are explored to develop and test strategies for peripheralization. The piperidine of 1 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.

SUBMITTER: Amato G

PROVIDER: S-EPMC6660994 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

Amato George G Wiethe Robert R Manke Amruta A Vasukuttan Vineetha V Snyder Rodney R Runyon Scott S Maitra Rangan R

Bioorganic & medicinal chemistry 20190704 16

Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (1) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (2) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients ...[more]

PMID: 31301950

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Project description:Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. Recently, the peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 KO mice. In this report, we systematically investigated gene expression changes in peripheral tissues of DIO mice treated with the CB1 inverse agonist AM251. CB1 receptor inhibition led to down-regulation of genes within the de novo fatty acid and cholesterol synthetic pathways, including SREBP-1 and -2, and their downstream targets in both liver and adipose tissue. In addition, genes involved in fatty acid Beta-oxidation were up-regulated with AM251 treatment, probably through the activation of PPARalpha. In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the TNFalpha signal transduction pathway and possibly to the activation of PPARgamma, both of which would result in improved insulin sensitivity. CB1-/- mice were obtained from A. Zimmer (University of Bonn) (Zimmer et al., 1999) and back-crossed onto C57BL/6J genetic background for ten generations by A. Zimmer before homozygous CB1-/- mice were re-derived at Taconic Farms (German Town, NY) onto the C57BL/6N genetic background. Male CB1-/- mice and control littermates (n=5-7 in each group) at 2 months of age were fed with regular chow (Teklad 7012, 13 % kcal from fat, 3.41 kcal/g, Harlan Laboratories, Indianapolis, IN, USA) or high fat diet (S3282, 59.4% kcal from fat; 24.5% kcal from carbohydrate; 16.2% kcal from protein; 5.29 kcal/g, Bio-Serv, Frenchtown, NJ, USA) for 14 weeks, and were individually caged 1 week before drug treatment. Vehicle (0.5% methylcellulose) or AM251 (10 mg/kg, Sigma, St Louis, MO, USA) were dosed by oral gavage at 5:00 PM daily for 2 days. Body weight was measured at 5:00 PM on day 1 and 2, and at 10:00 AM on day 3 before tissue collection. Food was measured at 5:00 PM on day 1 and at 10:00 AM on day 3 before tissue collection. Food intake is calculated as the difference in food weight at the start minus at the end of the study. Mice were euthanized by CO2 asphyxiation at 10:00 AM following the second dose.

Dataset Information

Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

Publications

Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

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