دورية أكاديمية
Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor.
| العنوان: | Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor. |
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| المؤلفون: | Richardson TI; Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. timrich@lilly.com, Ornstein PL, Briner K, Fisher MJ, Backer RT, Biggers CK, Clay MP, Emmerson PJ, Hertel LW, Hsiung HM, Husain S, Kahl SD, Lee JA, Lindstrom TD, Martinelli MJ, Mayer JP, Mullaney JT, O'Brien TP, Pawlak JM, Revell KD, Shah J, Zgombick JM, Herr RJ, Melekhov A, Sampson PB, King CH |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2004 Jan 29; Vol. 47 (3), pp. 744-55. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Print ISSN: 0022-2623 (Print) 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: | Piperazines/*chemical synthesis , Receptor, Melanocortin, Type 4/*agonists, Animals ; Binding, Competitive ; Biological Availability ; Cell Line ; Cyclic AMP/biosynthesis ; Humans ; Ligands ; Piperazines/chemistry ; Piperazines/pharmacology ; Radioligand Assay ; Rats ; Rats, Inbred F344 ; Receptor, Melanocortin, Type 4/metabolism ; Structure-Activity Relationship |
| مستخلص: | The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39. |
| المشرفين على المادة: | 0 (Ligands) 0 (Piperazines) 0 (Receptor, Melanocortin, Type 4) E0399OZS9N (Cyclic AMP) |
| تواريخ الأحداث: | Date Created: 20040123 Date Completed: 20040322 Latest Revision: 20131121 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1021/jm0304109 |
| PMID: | 14736255 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 0022-2623 |
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| DOI: | 10.1021/jm0304109 |