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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 me...

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Autores principales: Kusnetzow, Ana, Fowler, Melissa, Athanacio, Jon, Reinhart, Greg, Rico-Bautista, Elizabeth, Han, Sangdon, Kim, Sun Hee, Johns, Michael, Kredel, Taylor, Nguyen, Julie, Staley, Christine, Tan, Hannah, Luo, Rosa, Markison, Stacy, Madan, Ajay, Zhu, Yun Fei, Struthers, Scott, Betz, Stephen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552531/
http://dx.doi.org/10.1210/js.2019-SAT-364
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author Kusnetzow, Ana
Fowler, Melissa
Athanacio, Jon
Reinhart, Greg
Rico-Bautista, Elizabeth
Han, Sangdon
Kim, Sun Hee
Johns, Michael
Kredel, Taylor
Nguyen, Julie
Staley, Christine
Tan, Hannah
Luo, Rosa
Markison, Stacy
Madan, Ajay
Zhu, Yun Fei
Struthers, Scott
Betz, Stephen
author_facet Kusnetzow, Ana
Fowler, Melissa
Athanacio, Jon
Reinhart, Greg
Rico-Bautista, Elizabeth
Han, Sangdon
Kim, Sun Hee
Johns, Michael
Kredel, Taylor
Nguyen, Julie
Staley, Christine
Tan, Hannah
Luo, Rosa
Markison, Stacy
Madan, Ajay
Zhu, Yun Fei
Struthers, Scott
Betz, Stephen
author_sort Kusnetzow, Ana
collection PubMed
description 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.
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spelling pubmed-65525312019-06-13 SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats Kusnetzow, Ana Fowler, Melissa Athanacio, Jon Reinhart, Greg Rico-Bautista, Elizabeth Han, Sangdon Kim, Sun Hee Johns, Michael Kredel, Taylor Nguyen, Julie Staley, Christine Tan, Hannah Luo, Rosa Markison, Stacy Madan, Ajay Zhu, Yun Fei Struthers, Scott Betz, Stephen J Endocr Soc Adrenal 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. Endocrine Society 2019-04-30 /pmc/articles/PMC6552531/ http://dx.doi.org/10.1210/js.2019-SAT-364 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Adrenal
Kusnetzow, Ana
Fowler, Melissa
Athanacio, Jon
Reinhart, Greg
Rico-Bautista, Elizabeth
Han, Sangdon
Kim, Sun Hee
Johns, Michael
Kredel, Taylor
Nguyen, Julie
Staley, Christine
Tan, Hannah
Luo, Rosa
Markison, Stacy
Madan, Ajay
Zhu, Yun Fei
Struthers, Scott
Betz, Stephen
SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
title SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
title_full SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
title_fullStr SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
title_full_unstemmed SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
title_short SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
title_sort sat-364 nonpeptide orally-bioavailable acth antagonists: suppression of acth-induced corticosterone secretion and adrenal hypertrophy in rats
topic Adrenal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552531/
http://dx.doi.org/10.1210/js.2019-SAT-364
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