Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

Abstract

The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R) antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects. In the current study, a novel compound (TXX-522) was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A). Docking assays indicate that TXX-522 was bound with the CB1R in a mode similar to that of SR141716A. TXX-522 showed good binding, CB1R-selectivity (over the CB2R), and functional antagonist activities in a range of in vitro molecular and cellular assays. In vivo analysis of the steady state distribution of TXX-522 in the rat brain and blood tissues and the assay of its functional effects on CB1R activity collectively showed that TXX-522 showed minimal brain penetration. Moreover, the in vivo pharmacodynamic study further revealed that TXX-522 had good oral bioavailability and a potent anti-obesity effect, and ameliorated insulin resistance in high-fat diet-induced obese mice. No impact on food intake was observed in this model, confirming the limited brain penetration of this compound. Thus, the current study indicates that TXX-522 is a novel and potent peripherally acting selective CB1R antagonist with the potential to control obesity and related metabolic disorders.

Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice

“…Which include the developing of peripherally biased neutral antagonists and inverse agonists with limited central nervous system (CNS) permeability ( Janero, 2012 ). Several excellent lead compounds have been described in succession over the past few years, examples are the non-brain-penetrant neutral CB1R antagonist AM6545 and TXX-522, and the peripheral inverse agonists TM38837 and JD-5037 ( Cluny et al, 2010 ; Chorvat et al, 2012 ; Klumpers et al, 2013 ; Chen et al, 2017 ). Their anti-obesity effect and pharmacological mechanism of action are frequently evaluated in diet-induced obesity (DIO) or genetic obese rodent models ( Ravinet Trillou et al, 2003 ; Jourdan et al, 2010 ; Chen et al, 2017 ).…”

“…Several excellent lead compounds have been described in succession over the past few years, examples are the non-brain-penetrant neutral CB1R antagonist AM6545 and TXX-522, and the peripheral inverse agonists TM38837 and JD-5037 ( Cluny et al, 2010 ; Chorvat et al, 2012 ; Klumpers et al, 2013 ; Chen et al, 2017 ). Their anti-obesity effect and pharmacological mechanism of action are frequently evaluated in diet-induced obesity (DIO) or genetic obese rodent models ( Ravinet Trillou et al, 2003 ; Jourdan et al, 2010 ; Chen et al, 2017 ). However, to some extent, it’s difficult to accurately illuminate the peripheral mechanisms of action of the peripheral CB1R antagonists with these animal models, because it is hard to thoroughly preclude the impact of CNS, especially hypothalamus-associated roles in its effect.…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…Since the peripherally selective CB1 antagonist TM38837 was reported to elicit minimal CNS effects in humans [ 478 ], peripheral CB1R blockade may well be a viable therapeutic option for targeting metabolic disorders. In addition to promoting weight loss [ 479 , 480 , 481 , 482 , 483 ], peripherally selective CB1R antagonist/inverse agonist also demonstrated improvements in metabolic profiles [ 465 , 484 , 485 ] and liver function [ 486 ] in preclinical studies, thereby further highlighting the therapeutic utility of targeting the peripheral CB1R in metabolic syndromes. Interestingly, a dual therapy comprising of a peripheral CB1R antagonist with a CB2R agonist, was shown to be a highly effective strategy in the prevention of diabetes-related comorbidities in streptozocin-induced diabetic rats [ 487 ].…”

A patent update on cannabinoid receptor 1 antagonists (2015-2018)

“…Selective inhibition of CB1 receptor activity is a validated approach for treating obesity, diabetes, metabolic syndrome, dyslipidemias and liver diseases. 4,[7][8][9][10][11] Rimonabant (1, Figure 1), a CNS penetrating CB1 receptor inverse agonist developed by Sanofi-Aventis, was clinically approved in 2006 for the treatment of obesity in Europe, but was withdrawn in 2008 because of an increase in psychiatric disorders associated with antagonism of CB1 receptors in the CNS. 12 The adverse side effects seen with 1 precipitated the withdrawal of other CNS-penetrating CB1 receptor inverse agonists from clinical development, including otenabant (2, Figure 1); a compound developed by Pfizer.…”