252002-09-8Relevant articles and documents
Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety
Dhar, T. G. Murali,Nagarathnam, Dhanapalan,Marzabadi, Mohammad R.,Lagu, Bharat,Wong, Wai C.,Chiu, George,Tyagarajan, Sriram,Miao, Shou Wu,Zhang, Fengqi,Sun, Wanying,Tian, Dake,Shen, Quanrong,Zhang, Jack,Wetzel, John M.,Forray, Carlos,Chang, Raymond S. L.,Broten, Theodore P.,Schorn, Terry W.,Chen, Tsing Bao,O'Malley, Stacy,Ransom, Richard,Schneck, Kathryn,Bendesky, Robert,Harrell, Charles M.,Vyas, Kamlesh P.,Zhang, Kanyin,Gilbert, John,Pettibone, Douglas J.,Patane, Michael A.,Bock, Mark G.,Freidinger, Roger M.,Gluchowski, Charles
, p. 4778 - 4793 (2007/10/03)
We have previously described compound 1a as a high-affinity subtype selective α(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a μ-opioid agonist, 4-methoxycarbonyl-4- phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to μ-opioid activity. Modification of the linker gave several compounds with good {1a) binding affinity (K(i) = 300 fold over α(1b) and α(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant μ-opioid activity. Several of these compounds maintained good affinity at the α(1a) adrenoceptor and selectivity over α(1b) and α(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the μ-opioid receptor (IC50 > 30 μM vs 3 μM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (> 880-fold) over α(1b) and α(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro α(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.
