Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CB 1 R) Receptor with Reduced Lipophilicity.

التفاصيل البيبلوغرافية
العنوان:	Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CB 1 R) Receptor with Reduced Lipophilicity.
المؤلفون:	Iyer MR; Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Cinar R; Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Wood CM; Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Zawatsky CN; Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Coffey NJ; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Kim KA; Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Liu Z; Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Katz A; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Abdalla J; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States., Hassan SA; Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, United States., Lee YS; Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, United States.
المصدر:	Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 2374-2387. Date of Electronic Publication: 2022 Jan 27.
نوع المنشور:	Journal Article; Research Support, N.I.H., Intramural
اللغة:	English
بيانات الدورية:	Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة:	Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH:	Anti-Obesity Agents/therapeutic use , Cannabinoid Receptor Antagonists/therapeutic use , Obesity/drug therapy , Pyrazoles/therapeutic use , Receptor, Cannabinoid, CB1/*metabolism, Animals ; Anti-Obesity Agents/chemical synthesis ; Anti-Obesity Agents/metabolism ; Body Weight/drug effects ; Brain/metabolism ; Cannabinoid Receptor Antagonists/chemical synthesis ; Cannabinoid Receptor Antagonists/metabolism ; Diet, High-Fat ; Drug Inverse Agonism ; Hydrophobic and Hydrophilic Interactions ; Male ; Mice, Inbred C57BL ; Molecular Structure ; Pyrazoles/chemical synthesis ; Pyrazoles/metabolism ; Stereoisomerism ; Structure-Activity Relationship ; Mice
مستخلص:	In the present report, we describe the synthesis and structure-activity relationships of novel "four-arm" dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CB 1 R). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB 1 receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CB 1 R and potent in vitro CB 1 R antagonist activities. Promising compounds with potent CB 1 R activity were evaluated in tissue distribution studies. Compounds 6a , 6f , and 7c showed limited brain penetrance attesting to its peripheral restriction. The 4 S -enantiomer of these compounds further showed a stereoselective affinity for the CB 1 receptor and behaved as inverse agonists. In vivo studies on food intake and body weight reduction in diet-induced obese (DIO) mice showed that these compounds could serve as potential leads for the development of selective CB 1 R antagonists with improved potency and peripheral restriction.
المشرفين على المادة:	0 (Anti-Obesity Agents) 0 (Cannabinoid Receptor Antagonists) 0 (Pyrazoles) 0 (Receptor, Cannabinoid, CB1)
تواريخ الأحداث:	Date Created: 20220127 Date Completed: 20220218 Latest Revision: 20240226
رمز التحديث:	20240226
DOI:	10.1021/acs.jmedchem.1c01836
PMID:	35084860
قاعدة البيانات:	MEDLINE

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الوصف
تدمد:	1520-4804
DOI:	10.1021/acs.jmedchem.1c01836