Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.

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Lagu B, Tian D, Nagarathnam D, Marzabadi MR, Wong WC, Miao SW, Zhang F, Sun W, Chiu G, Fang J, Forray C, Chang RS, Ransom RW, Chen TB, O'Malley S, Zhang K, Vyas KP, Gluchowski C

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.

J Med Chem. 1999 Nov 18;42(23):4794-803.

PubMed ID

10579842 [ View in PubMed

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Abstract

Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) 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 mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-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 mu-opioid receptor.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Terazosin	Alpha-1A adrenergic receptor	Ki (nM)	6.9	N/A	N/A	Details
Terazosin	Alpha-1B adrenergic receptor	Ki (nM)	1.9	N/A	N/A	Details
Terazosin	Alpha-1D adrenergic receptor	Ki (nM)	3.5	N/A	N/A	Details