Novel Cannabinoid Receptor Modulators

National Institute On Alcohol Abuse And Alcoholism

Investigators

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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, the 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. This series of compounds were named as cannabinoformins as they contain an embedded biguanide moiety seen in the anti-diabetic drug metformin. The current series of novel compounds were expected to primarily modulate CB1R receptors and act as functional antagonists/inverse agonists. Investigation of biguanide compounds herein revealed varying binding affinity and functional potency for CB1R. SAR clearly showed that molecules substituted with an electron withdrawing group or an acyl group on the guanidine moiety attached to the main chemical scaffold show very high CB1R binding affinity, retain potent antagonism with inverse agonism for the CB1R. Attesting to the design features, the compounds showed activation of AMPK in recombinant assays. Select racemates were further reevaluated by separation into chiral components. Stereoselective affinity and potency for the CB1R resided in the S-eutomer as seen in case of MRI-1887 where single crystal X-ray structure showed that the CB1 active enantiomer has S-stereochemistry at the C4 position. As expected, enzymatic AMPK activation was seen for both enantiomers. Brain penetrance was evaluated via tissue distribution studies. Compounds MRI-1776 and MRI-1887 showed less than 5% brain penetration in tissue distribution studies upon oral gavage indicating good oral exposure. Both MRI-1776 and MRI-1887 were orally available with good in vitro ADME and PK properties along with increased tPSA, lower CLogP values and CNS MPO scores <3.0 indicating impaired brain penetrance when compared to rimonabant as well as SLV319. The aminoalkylsulfonyl modification in compounds (e.g MRI-1950) further increased the polar surface area and options for improving aqueous solubility. This set of compounds also showed AMPK activation along with potent CB1R antagonism. However tested compounds had low plasma concentration upon oral gavage indicating limited oral bioavailability. T Both MRI-1776 and MRI-1887 showed liver tissue exposure over 50 M after 10 mg/kg acute oral administration. Since both compounds activate AMPK in the submicromolar range. Acute treatment with MRI-1776 and MRI-1887 increased AMPK activity in vivo in liver. Higher liver exposure of MRI-1776 together with higher potency for AMPK activation around 0.1 M makes it better candidate as a cannabinoformin to use in vivo studies. This also suggested tissue specific dual targeting of CB1R antagonism and AMPK activation with the presented cannabinoformin compounds depends on their target tissue exposure and PK/PD relationships. As a test of preliminary efficacy, in a weekly treatment of daily intraperitoneal injections with MRI-1776 and MRI-1887 in diet-induced obese (DIO) mice under a metabolic chamber paradigm, reduced body weight and food intake were observed due to potent peripheral CB1R antagonism. A prominent increase in fat oxidation was also observed for the tested compounds which could indicate a putative role of AMPK activation. Both compounds MRI-1776 and MRI-1887 had acceptable half-life and good metabolic stability. Compound MRI-1776 when further tested in an acute DIO model, upon oral administration showed reduction in food-intake, body weight, improvement in glucose tolerance and insulin sensitivity. MRI-1776 also showed an increase in fat oxidation in CB1 knockout mice attesting to the engagement of the secondary target (AMPK). This work has now been published in J. Med. Chem 2023, ASAP. MRI-1776 also produced a decrease in alcohol consumption in a 2-bottle choice paradigm. Both cannabinoformin compounds MRI-1776 and MRI-1887 could serve as potential leads for treatment of metabolic syndrome disorders (licensed by Inversago Pharma). Future studies involving the above compounds in chronic treatment paradigms will be explored along with their efficacy in ameliorating fibrosis in murine models of lung and liver. An additional candidate arising from this work, MRI-1891/INV202 along with MRI-1776/INV-201 has been licensed by Inversago Pharma. MRI-1891/INV202 has shown a clean profile and safety in a Phase-I trial and is currently in a Phase-II clinical trial for diabetic nephropathy. The Phase-1B study results for MRI-1891 have been revealed now with the compound showing promising effects in lowering body weight (3.5 kg) over a 28-day period that exceeds GLP-1 and GLP-1/GIP agonists (1.7-2.0 kg). A 25 mg QD PO INV202 for 28 days also showed promising effects in lowering trigylcerides, LDL and VLDL as compared to placebo treatment. (Update: MRI-1891/INV202 will now be developed by Novo Nordisk as a result of their acquisition of Inversago Pharma and its CB1 compounds pipeline including our in-house generated compounds)