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Design, Synthesis, and Biological Evaluations of Novel Thiazolo[4,5-d]pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists as Potential Treatments for Stress Related Disorders and Congenital Adrenal Hyperplasia (CAH).

التفاصيل البيبلوغرافية
العنوان: Design, Synthesis, and Biological Evaluations of Novel Thiazolo[4,5-d]pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists as Potential Treatments for Stress Related Disorders and Congenital Adrenal Hyperplasia (CAH).
المؤلفون: Islam MR; Department of Pharmaceutical Science, College of Pharmacy & Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA., Markatos C; Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece., Pirmettis I; Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research 'Demokritos', 15310 Athens, Greece., Papadopoulos M; Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research 'Demokritos', 15310 Athens, Greece., Karageorgos V; Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece., Liapakis G; Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece., Fahmy H; Department of Pharmaceutical Science, College of Pharmacy & Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA.
المصدر: Molecules (Basel, Switzerland) [Molecules] 2024 Aug 01; Vol. 29 (15). Date of Electronic Publication: 2024 Aug 01.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c1995-
مواضيع طبية MeSH: Receptors, Corticotropin-Releasing Hormone*/antagonists & inhibitors , Receptors, Corticotropin-Releasing Hormone*/metabolism , Pyrimidines*/chemistry , Pyrimidines*/pharmacology , Pyrimidines*/chemical synthesis , Drug Design* , Adrenal Hyperplasia, Congenital*/drug therapy , Adrenal Hyperplasia, Congenital*/metabolism, Humans ; Pyrroles/chemistry ; Pyrroles/chemical synthesis ; Pyrroles/pharmacology ; Corticotropin-Releasing Hormone/metabolism ; Stress, Psychological/drug therapy ; Molecular Docking Simulation
مستخلص: Corticotropin-releasing factor (CRF) is a key neuropeptide hormone that is secreted from the hypothalamus. It is the master hormone of the HPA axis, which orchestrates the physiological and behavioral responses to stress. Many disorders, including anxiety, depression, addiction relapse, and others, are related to over-activation of this system. Thus, new molecules that may interfere with CRF receptor binding may be of value to treat neuropsychiatric stress-related disorders. Also, CRF 1 R antagonists have recently emerged as potential treatment options for congenital adrenal hyperplasia. Previously, several series of CRF 1 receptor antagonists were developed by our group. In continuation of our efforts in this direction, herein we report the synthesis and biological evaluation of a new series of CRF 1 R antagonists. Representative compounds were evaluated for their binding affinities compared to antalarmin. Four compounds ( 2 , 5 , 20 , and 21 ) showed log IC 50 values of -8.22, -7.95, -8.04, and -7.88, respectively, compared to -7.78 for antalarmin. This result indicates that these four compounds are superior to antalarmin by 2.5, 1.4, 1.7, and 1.25 times, respectively. It is worth mentioning that compound 2 , in terms of IC 50 , is among the best CRF 1 R antagonists ever developed in the last 40 years. The in silico physicochemical properties of the lead compounds showed good drug-like properties. Thus, further research in this direction may lead to better and safer CRF receptor antagonists that may have clinical applications, particularly for stress-related disorders and the treatment of congenital adrenal hyperplasia.
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فهرسة مساهمة: Keywords: CRF receptor antagonists; antalarmin; congenital adrenal hyperplasia (CAH); thiazolo[4,5-d]pyrimidines
المشرفين على المادة: 0 (Receptors, Corticotropin-Releasing Hormone)
0 (Pyrimidines)
5CLY6W2H1M (CRF receptor type 1)
0 (Pyrroles)
0 (antalarmin)
9015-71-8 (Corticotropin-Releasing Hormone)
تواريخ الأحداث: Date Created: 20240810 Date Completed: 20240810 Latest Revision: 20240918
رمز التحديث: 20240918
مُعرف محوري في PubMed: PMC11314199
DOI: 10.3390/molecules29153647
PMID: 39125051
قاعدة البيانات: MEDLINE
الوصف
تدمد:1420-3049
DOI:10.3390/molecules29153647