Molecule of the Month (2007)

An orally bioavailable MC4 antagonist with in vivo efficacy in animal models of cachexia. Cachexia is defined as a loss of weight, muscle atrophy and fatigue coupled with an extreme loss of appetite in an individual not actively attempting to lose weight [1]. Often seen in end-stage cancer, cachexia is often referred to as ‘cancer cachexia’ in this context and physically weakens cancer patients to a state of immobility [1]. Moreover, cancer cachexia significnatly impacts patients quality of life, diminishes their response to standard chemotherapy and leads to increased rates of morbitiy and mortality [1-3]. Sadly, the currently available treatments for cancer cachexia are not very effective [1-3]. Recently, Chen and co-workers from Neuocrine Biosciences reported (J. Med. Chem. 2007, 50, 5249-5252) on a potential new treatment for cancer cachexia by antagonism of the melanocortin-4 receptor (MC4R) with an orally bioavailble small molecule [3]. The MC4 receptor is a member of the class A G protein-coupled receptor (GPCR) family and there are five subtypes of melanocortin receptors (MC1-5). MC4 is expressed in various regions of the brain, and plays a critical role in regulating feeding behavior and energy homeostatsis in both animals and humans [3]. MC4 agonists have been shown to suppress food intake and reduce body weight in animals, suggesting agonim of MC4 may be a theraputic approach for the treatment of obesity [3]. In contrast, MC4 antagonists have been demonstarted to promote food intake and increase weight gain [3]. After extensive lead optimization efforts, Chen and co-workers identified 1, of 1-{2-[(1S)-(3-dimethylaminopropionyl)amino-2- methylpropyl]-4-methylphenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)- propionyl]piperazine, a potent (MC4 Ki = 2.8 nM, IC50 = 35 nM) and selective ( > 125-fold selective versus MC1, MC3, MC5) MC4 antagonist [3]. MC4 antagonist 1 possessed excellent aqueous solubility ( > 33 mg/mL at pH 7 and > 71 mg/mL at pH 3), a good metabolic profile (no significant CYP inhibition, not a P-gp substrate (B/A-A/B = 1.9)) and good oral bioavailability (32%) in mice (as well as across species: rat, 43%, dog, 19%, rhesus, 19%). Despite a low to moderate brain/plasma ratio of 0.17 (based on AUCs), MC4 antagonist 1 significantly increased food intake on days 10-12 in Lewis lung carcinoma (LLC) tumor-bearing mice when dosed at either 5 or 20 mg/kg p.o. compared to tumor-bearing vehicle treated animals. Thus, selective antagonism of MC4 with small molecules holds promise as a potential new treatment for patients suffering from cancer cachexia, a truly unmet medical need. REFERENCES [1] www.wikipedia.com search string: cachexia [2] Bossola, M.; Pacceli, F.; Tortorelli, A.; Doglietto, G.B. ‘Cancer cachexia: Its time for more clinical trials’ Ann. Surg. Oncol. 2007, 14, 276-285. [3] Chen, C.; Jiang, W.; Tucci, F.; Tran, J.A.; Fleck, B.A.; Hoare, S.R.; Joppa, M.; Markison, S.; Wen, J.; Sai, Y.; Johns, M.; Madam, A.; Chen, T.; Chen, C.W.; Marinkovic, D.; Arellano, M.; Saunders, J. Foster, A.C. ‘Discovery of 1-{2-[(1S)-(3-dimethylaminopropionyl) amino-2-methylpropyl]-4-methylphenyl}-4-(2R)-methyl-3-(4-chlorophenyl)- propionyl]piperazine as an orally active antagonist of the melanocortin receptor for the potential treatment of cachexia’ J. Med. Chem. 2007, 50, 5249-5252, and references therein.