Novel Cannabinoid Receptor Modulators

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications & trials

Abstract

SMC was started as an independent section in January of 2021. The main goals of the Section on Medicinal Chemistry are to design and discover novel drugs and therapeutics for the treatment of inflammatory and fibrotic disorders. The Arachidonic acid (AA) pathway is a major biosynthetic pathway with various mediators that are targets for disease treatments. AA and other polyunsaturated fatty acids (PUFAs) are also the substrates of various oxygenases (Cox/Lox) and cytochrome P450 enzymes (P450), whose end-products include leukotrienes, lipoxins, and epoxyeicosatrienoic acids (EETs). Endocannabinoids are discrete endogenous compounds, which are formed from arachidonate-containing phospholipids that are cleaved to arachidonic acid by enzymes like fatty acid amide hydrolase (FAAH). The endocannabinoid system is involved in the regulation of many physiological and pathological processes related to food and drug intake, body weight, immune system and metabolism. Exogenous ligands that activate or antagonize the endocannabinoid receptors, mainly CB1 and CB2, thus have great value in treating human diseases like pain, obesity, fibrosis and other metabolic syndrome (MetS) disorders. Current work in our laboratory involves the design and synthesis of ligands that act on CB1 and CB2 receptors. One of our objectives involves the design and biological evaluation of functional antagonists at the CB1 receptor. The rationale for this work comes from studies over the past two decades from various labs which show that global blockade of CB1 receptors results in reduced food intake and alleviation of metabolic complications arising from obesity and insulin resistance. Based on this paradigm, rimonabant became the first-in-class molecule approved in the EU as an anti-obesity drug. Unfortunately, rimonabant's use in the clinic was short-lived as target engagement/blockade of brain CB1 receptors contributed to anxiogenic and other psychiatric side-effects. This prompted the halt on clinical development for many molecules based on global CB1 antagonism. In recent years, work from the lab of Kunos et al. has shown that peripheral blockade of CB1 receptors retains many metabolic benefits without CNS side-effects in murine models. This has paved the way for renewed and as yet untapped potential for selective, peripheral CB1 antagonism-based therapy in treating human diseases. Previously we have designed and synthesized new analogs of peripherally-restricted pyrazole-scaffold based dual-target inhibitors of the inducible nitric oxide synthase (iNOS) and CB1. An optimized lead candidate MRI-1867 and a back-up candidate MRI-1569 have shown promising effects in reducing body weight, ameliorating glucose tolerance and superior anti-fibrotic affects in mouse models. The candidate drug has been licensed and is currently in a Phase-1 clinical trial in Canada. In a related strategy we have also designed and synthesized peripherally-restricted CB1 antagonists which act as adenosine mono-phosphate kinase (AMPK) activators. In collaboration with the Section on Fibrotic Disorders (SFD), two compounds MRI-1776 and MRI-1891 are currently being evaluated in pre-clinical models of lung and liver fibrosis. In collaboration with SFD and LPS we have also shown that MRI-1891 is a potent, functionally selective, beta-arrestin-2 biased antagonist of CB1 antagonist with two-fold selectivity over G-protein signaling. The details of this work are now published. (Liu et al, ACS Pharmacol. Trans. Sci, 2021). In continuation with the development of novel CB1 antagonists, we have designed and synthesized novel dihydropyrazoline compounds and studied their structure-activity relationships. A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB1 receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, elicited potent in vitro CB1R antagonist activities. Promising compounds with potent CB1R activity were evaluated in tissue distribution studies. Three compounds showed limited brain penetrance (<4%). Chiral HPLC separation and small molecule X-ray crystallization of one enantiomer of the diethylaminosulfonyl analogue showed that the CB1 potency resides with the 4S eutomer. The 4S-eutomer compounds showed high affinity for CB1 receptor and behaved as inverse agonists at the CB1 receptor. These compounds could serve as potential leads for the development of selective CB1 antagonists with improved potency and peripheral restriction (Iyer et al J Med Chem 2022). Continuing with our goals of developing peripherally-restricted CB1 antagonists, we have synthesized highly potent analogs of the derivatized N-piperdinyl analogs which are now being pharmacologically evaluated for new functional profiles. In addition, we are also evaluating the structure-activity relationships of a new series of analogs for CB1 functional antagonism. An additional goal of the SMC lab involves the design and synthesis of CB2 modulators and its role in disease mediated pathways. Compound MRI-2594 (Li et al., 2019, Cell 176, 459467) is now being studied in in vivo rodent models where CB2-agonism based mechanism can alleviate pathogenic pathways. We have also begun to study the role of the cytochrome P450 enzyme-mediated pathway and its role in pathophysiological conditions. We have designed, synthesized and evaluated novel soluble epoxide hydrolase inhibitors for the treatment of pain and inflammatory pathways. The details from this work will be reported in subsequent reports. Ultimately our goal is to develop tools for precision polypharmacology with the above mentioned targets that would offer personalized therapies for treating complex diseases. The lab is also interested in developing novel synthetic methodology to expand the biologically relevant chemical space. In this approach we have now developed a novel, one-pot synthetic sequence for oxo-edits to sulfur atom, based on a modified Bunte salt approach in sulfonylurea molecules. The reaction utilizes a sequential one-pot generation of an imidoylchloride, followed by a putative Bunte salt formation, which upon extrusion of sulfur trioxide creates a new CS bond. In continuation of the sequence common sulfonyl thiourea intermediates could be alkylated in the same pot to various sulfur pendant side chains. We have demonstrated a high sulfonylurea substrate tolerance of this method and its application to diverse chiral and achiral de novo sulfur-containing drug-like molecules (Iyer et al ACS Omega, ASAP). A further validation of this protocol was achieved by a successful application of this strategy in a high-yield synthesis of potent dihydropyrazoline class of cannabinoid antagonist, which was enabled by a key diastereomeric intermediate bearing a chiral isothiourea handle. An added advantage of this protocol is the use of cheap inorganic thiosulfate under aqueous conditions with clean, isolable products under controlled temperatures and solvents employed. The robust and expedient reaction conditions along with adaptable precursors in this transformation will help expand the underexplored chemical space of isothio-based (chiral) analogs and provide downstream access to manipulate S-oxidation states or utilizing them as decoy substrates for synthetic transformations.