Design and Synthesis of Novel α1a Adrenoceptor-Selective Antagonists. 3. Approaches To Eliminate Opioid Agonist Metabolites by Using Substituted Phenylpiperazine Side Chains
- 27 October 1999
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 42 (23) , 4794-4803
- https://doi.org/10.1021/jm990202+
Abstract
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.Keywords
This publication has 9 references indexed in Scilit:
- 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 MoietyJournal of Medicinal Chemistry, 1999
- Design and Synthesis of Novel α1a Adrenoceptor-Selective Antagonists. 1. Structure−Activity Relationship in DihydropyrimidinonesJournal of Medicinal Chemistry, 1999
- Pharmacological Options in the Treatment of Benign Prostatic HyperplasiaJournal of Medicinal Chemistry, 1997
- Discovery of .alpha.1a-Adrenergic Receptor Antagonists Based on the L-Type Ca2+ Channel Antagonist NiguldipineJournal of Medicinal Chemistry, 1995
- Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasiaUrology, 1995
- Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacyJournal of Medicinal Chemistry, 1989
- The genomic clone G-21 which resembles a β-adrenergic receptor sequence encodes the 5-HT1A receptorNature, 1988
- Specific binding of 3H-tiotidine to histamine H2 receptors in guinea pig cerebral cortexNature, 1983
- HETEROGENEITY OF HISTAMINE Hi‐RECEPTORS: SPECIES VARIATIONS IN [3H]MEPYRAMINE BINDING OF BRAIN MEMBRANESJournal of Neurochemistry, 1979