200052-33-1Relevant articles and documents
Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains
Lagu, Bharat,Tian, Dake,Nagarathnam, Dhanapalan,Marzabadi, Mohammad R.,Wong, Wai C.,Miao, Shou W.,Zhang, Fengqi,Sun, Wanying,Chiu, George,Fang, James,Forray, Carlos,Chang, Raymond S. L.,Ransom, Richard W.,Chen, Tsing B.,O'Malley, Stacey,Zhang, Kanyin,Vyas, Kamlesh P.,Gluchowski, Charles
, p. 4794 - 4803 (1999)
Dihydropyrimidinones, such as 1, represent a novel class of α(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of I 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.
