SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats

Cushing’s disease is most commonly the result of a microadenoma derived from pituitary corticotrophic cells that secretes excess adrenocorticotropic hormone (ACTH). ACTH is an important modulator of steroidal hormone synthesis and secretion from the adrenal gland and its selective activity at the melanocortin type 2 receptor (MC2) dictates the synthesis and secretion of cortisol (corticosterone in rats). The resulting hypercortisolemia in Cushing’s patients presents in a myriad of symptoms that include growth of fat pads, excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease, among others that result in high morbidity. We hypothesize that blocking ACTH action directly via a selective MC2 receptor antagonist may provide an important new therapeutic mechanism to help better manage Cushing’s disease in patients. To test this hypothesis, we launched an iterative medicinal chemistry program to identify potent and selective nonpeptide MC2 receptor antagonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials. Unlike most other G protein coupled receptors, MC2 requires the presence of an accessory protein (MRAP) for cell surface expression and recognition of ACTH and our effort led to small molecule nonpeptides with antagonist activity in CHO-K cells stably expressing the MC2-MRAP complex. Iterative optimization led rapidly to the discovery of multiple chemical classes of highly potent, nonpeptide MC2 selective antagonist leads, which were then further optimized for drug-like characteristics. We have identified multiple compounds that exhibit high potency for human and rat MC2 receptors (hMC2 K(b) <1 nM), while having little activity at the MC1, MC3, MC4, or MC5 receptors. In rat and dog pharmacokinetic studies, many of these selective MC2 antagonists exhibit good oral bioavailability. In rat models to probe their efficacy, these selective MC2 antagonists acutely suppress corticosterone secretion in an ACTH-challenge model in male Sprague-Dawley rats and the degree of suppression is proportional to their activity at the rat MC2 receptor. In a 7-day hypercortisolemia model in which rats receive an implanted minipump that continually secretes ACTH, corticosterone levels were decreased, and body weight loss and adrenal hypertrophy were prevented. To our knowledge, these compounds represent the first potent nonpeptide MC2 receptor antagonists to demonstrate in vitro potency and in vivo efficacy and we are actively pursuing preclinical safety and toxicology studies to select the optimal molecule(s) suitable for evaluation in human clinical trials.