Cushing’s disease (CD) and Ectopic ACTH syndrome (EAS) stem from excess circulating adrenocorticotropic hormone (ACTH) and resulting hypercortisolemia. In CD, excess ACTH is secreted from pituitary tumors, whereas excess ACTH in EAS arises from nonpituitary tumors. ACTH acts on the adrenal melanocortin type 2 (MC2) receptor to control the synthesis and secretion of adrenal hormones, including the stress hormone cortisol (corticosterone in rats) which accounts for the comorbidities of CD and EAS. Availability of a potent ACTH antagonist that can normalize cortisol in patients with diseases of excess ACTH will be a major advance in endocrinology. Additionally, an ACTH antagonist will have utility in congenital adrenal hyperplasia (CAH) because of its ability to block production of excess adrenal androgens. Crinetics is evaluating and developing ACTH antagonists for the treatment of diseases of excess ACTH. To our knowledge, these compounds represent the first potent nonpeptide ACTH antagonists to demonstrate in vitro potency and in vivo efficacy. As a result, the direct effects of sustained MC2 receptor blockade on the structure and function of the adrenal gland have never been able to be assessed. We examined the effects of several orally bioavailable ACTH antagonists across a range of doses on Sprague-Dawley rat adrenal gland weight, histology, and hormone levels in repeat dosing (7-14 days) studies. Sustained MC2 receptor antagonism dose dependently blocked activity of ACTH at the level of the adrenal gland and reduced plasma corticosterone levels. In the normal rat, this resulted in dose-dependent atrophy of the adrenal gland as assessed by organ weights and microscopically. The atrophy was primarily observed in the cortisol producing zona fasciculata, as well as in the zona reticularis, with smaller reductions noted in the aldosterone producing zona glomerulosa. Additionally, hypertrophy of the adrenal glands caused by continuous subcutaneous administration of exogenous ACTH was reversed by treatment with an ACTH antagonist. The adrenal effects were accompanied by expected changes in corticosterone levels. These preclinical findings demonstrate the therapeutic potential of ACTH antagonism and provide a strong rationale for development of an orally bioavailable drug that can be used to combat CD, EAS, and CAH.

Background. Obesity and Insulin resistance (IR) are conditions that cause metabolic disorders and secondary effects, including musculoskeletal complications making tendon prone to lesions. Antidiabetic drugs presents several side effects, making fundamental the pursue of alternative treatments, to improve patient's quality of life. Resveratrol (RSV) can re-establish insulin sensitivity and regulate glycemic levels. It also presents a range of other biological properties such as: antioxidant, anti-inflammatory, neuroprotective, anti-aging, anti-cancer, prevention of cardiovascular disease, and improvement in mitochondrial function. The study evaluates RSV's effects in the calcaneal tendon in insulin-resistant obese animals. Methods. 40 male mice (C5B16) were distributed in 8 groups: Non-obese Control; Non-obese Insulin-treated; Non-obese RSV-treated; Non-obese Insulin and RSV-treated; Obese; Obese insulin-treated; Obese RSV-treated; Obese Insulin and RSV-treated. IR was induced by a hyperlipidemic AIN-93 diet and attested through an insulin tolerance test. RSV was administered daily via gavage (100 mg/kg) for two weeks, starting on the 10 th week of life until euthanasia, when tendons were removed for testing. Results. Resveratrol treatment demonstrated a protective effect over tendons in obese, insulin-resistant animals, reducing the activity of different MMPs, MMP-2, and MMP-9, and avoiding protein content reduction, maintaining its levels similar to healthy animals. Conclusions. Resveratrol treatment reduces the activity of, MMP-2 and MMP-9, and also avoids protein content degradation. Its effects over inflammation could be helpful addressing IR patients, helping not only to control the disease, but also making the tendon lesion treatment more efficient.

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