Design and Synthesis of Novel α1a Adrenoceptor-Selective Antagonists. 2. Approaches To Eliminate Opioid Agonist Metabolites via Modification of Linker and 4-Methoxycarbonyl-4-phenylpiperidine Moiety

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Abstract
We have previously described compound 1a as a high-affinity subtype selective α1a 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 α1a binding affinity (Ki = < 1 nM) and selectivity (>300-fold over α1b and α1d). 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 α1a adrenoceptor and selectivity over α1b and α1d. 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 α1b and α1d, 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 Kbs comparable to their in vitro α1a binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP Kb/IUP Kb > 20-fold) in the in vivo experiments in dogs, similar to 1a.