Author: Receveur, Jean‐Marie ; Andersson, Gunnar ; Linget, Jean‐Michel ; Högberg, Thomas ; Elling, Christian E. ; Cooper, Martin E. ; Nørregaard, Pia K.

Background and PurposeThe cannabinoid CB1 receptor has a well‐established role in appetite regulation. Drugs antagonizing central CB1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet‐induced obese (DIO) mice for 5 weeks at doses for which CNS‐mediated effects were minimal.Experimental ApproachCompounds were tested in dose–response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study.Key ResultsTM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake.Conclusion and ImplicationsWeight loss and metabolic benefits of TM38837 are likely not CNS‐mediated but could be linked to enhanced liver exposure, which implicates intracellular CB1 receptors in hepatocytes as a possible driver of obesity and co‐morbidities.

01 Jan 2024·Bioorganic & Medicinal Chemistry Letters

Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837

Article

Author: Högberg, Thomas ; Cooper, Martin ; Linget, Jean-Michel ; Little, Paul B ; Receveur, Jean-Marie ; Murray, Anthony ; Nørregaard, Pia K

Several series of diverse pyrazole-3-carboxamides functionalized with 4-methylamides, 4-methylcarboxylic acids and 4-methyltetrazoles were prepared from the corresponding 4-cyanomethylpyrazoles and investigated as Cannabinoid receptor 1 (CB1) antagonists and inverse agonists with the aim of making compounds with less CNS (Central Nervous System) mediated side-effects compared to rimonabant. The compounds were evaluated and optimized with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers of inflammation and glucose homeostasis, at doses apparently producing negligible brain exposure. TM38837 became the first peripherally restricted CB1 antagonist or inverse agonist to enter clinical trials supporting its lack of CNS effects and it is now believed that the non-CNS mediated efficacy is linked to high liver exposure. This opens opportunities to be explored in other indications such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Note that this is a first-time disclosure of the structure of TM38837 and other structures appearing in literature are not connected with this program.

01 Mar 2014·SynapseQ4 · MEDICINE

Low brain CB1 receptor occupancy by a second generation CB1 receptor antagonist TM38837 in comparison with rimonabant in nonhuman primates: A PET study

Q4 · MEDICINE

Article

Author: Varnäs, Katarina ; Halldin, Christer ; Takano, Akihiro ; Little, Paul Brian ; Noerregaard, Pia K. ; Gulyás, Balázs ; Elling, Christian e. ; Jensen, Niels Ole

ABSTRACTBoth central and peripheral cannabinoid receptor type 1 (CB1R) have been considered to be among the key targets for obesity treatment. First generation CB1R antagonists/inverse agonists such as rimonabant and taranabant exhibited severe CNS side effects such as anxiety and depression, which are considered to be related to the compounds' ability to access central CB1R. Recently, several compounds have been developed as second generation antagonists with a profile of restriction to peripheral CB1R. We evaluated the distribution of TM38837, a second generation CB1R antagonist, using brain and whole body PET in three cynomolgus monkeys, and established the relationship between CB1R occupancy and dose/plasma concentration of TM38837 in comparison with rimonabant. A brain PET study was performed using [11C]MePPEP, a PET radioligand for CB1R, to evaluate the brain CB1R occupancy of TM38837 at various plasma concentrations in comparison with rimonabant at known efficacious plasma concentrations. A whole body PET study was performed to investigate the change of peripheral distribution of [11C]MePPEP by TM38837 administration, which indirectly estimated the effects to the peripheral CB1R by TM38837. CB1R occupancy by both TM38837 and rimonabant increased in a dose/plasma concentration‐dependent manner. However, in vivo affinity by plasma level was more than 100 times lower for TM38837. Peripherally, [11C]MePPEP accumulation decreased in gall bladder and brown adipose tissue by TM38837 administration. TM38837 showed rather lower CB1R occupancy than rimonabant at the expected therapeutic plasma level, which is expected to reduce CNS side effects in clinical situations. Further clinical development of TM38837 is warranted. Synapse 68:89–97, 2014. © 2013 Wiley Periodicals, Inc.

100 Deals associated with TM-38837

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 1	DK	7TM Pharma	-
Obesity	Phase 1	DK	7TM Pharma	-

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