Design and Synthesis of Novel α1a Adrenoceptor-Selective Antagonists. 3. Approaches To Eliminate Opioid Agonist Metabolites by Using Substituted Phenylpiperazine Side Chains
| العنوان: | Design and Synthesis of Novel α1a Adrenoceptor-Selective Antagonists. 3. Approaches To Eliminate Opioid Agonist Metabolites by Using Substituted Phenylpiperazine Side Chains |
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| المؤلفون: | Carlos Forray, Tsing B. Chen, Raymond S. L. Chang, Stacey O'Malley, Dhanapalan Nagarathnam, George Chiu, Dake Tian, Miao Shou Wu, Wai C. Wong, Bharat Lagu, Richard W. Ransom, Mohammad R. Marzabadi, Kanyin Zhang, Kamlesh P. Vyas, Charles Gluchowski, James Fang, Wanying Sun, Fengqi Zhang |
| المصدر: | Journal of Medicinal Chemistry. 42:4794-4803 |
| بيانات النشر: | American Chemical Society (ACS), 1999. |
| سنة النشر: | 1999 |
| مصطلحات موضوعية: | Agonist, medicine.drug_class, Stereochemistry, Metabolite, Carboxamide, Phenylpiperazine, Chemical synthesis, chemistry.chemical_compound, chemistry, Drug Discovery, medicine, Molecular Medicine, Moiety, Receptor, Lead compound |
| الوصف: | Dihydropyrimidinones, such as 1, represent a novel class of α1a adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the μ-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the μ-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the μ-opioid receptor. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990202+ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::c31af145a78e8fe8e37099a3289b08a5 https://doi.org/10.1021/jm990202+ |
| رقم الانضمام: | edsair.doi...........c31af145a78e8fe8e37099a3289b08a5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm990202+ |