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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
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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. |
format | Online Article Text |
id | pubmed-6552531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
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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