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

B Lagu; D Tian; D Nagarathnam; M R Marzabadi; W C Wong; S W Miao; F Zhang; W Sun; G Chiu; J Fang; C Forray; R S Chang; R W Ransom; T B Chen; S O'Malley; K Zhang; K P Vyas; C Gluchowski

doi:10.1021/jm990202+

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. doi: 10.1021/jm990202+.

Authors

B Lagu¹, D Tian, D Nagarathnam, M R Marzabadi, W C Wong, S W Miao, F Zhang, W Sun, G Chiu, J Fang, C Forray, R S Chang, R W Ransom, T B Chen, S O'Malley, K Zhang, K P Vyas, C Gluchowski

Affiliation

¹ Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.

PMID: 10579842
DOI: 10.1021/jm990202+

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.

MeSH terms

Adrenergic alpha-Antagonists / chemical synthesis*
Adrenergic alpha-Antagonists / chemistry
Adrenergic alpha-Antagonists / metabolism
Adrenergic alpha-Antagonists / pharmacology
Animals
Binding, Competitive
Biological Availability
Dogs
Drug Design
GTP-Binding Proteins / metabolism
Half-Life
Humans
In Vitro Techniques
Male
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / metabolism
Piperazines / pharmacology
Prostate / metabolism
Pyrimidinones / chemical synthesis*
Pyrimidinones / chemistry
Pyrimidinones / metabolism
Pyrimidinones / pharmacology
Rats
Receptors, Adrenergic, alpha-1 / metabolism*
Receptors, Opioid, mu / agonists
Recombinant Proteins / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

1,2,3,6-tetrahydro-1-(N-((4-(2-nitrophenyl)piperazin-1-yl)propyl)carboxamido)-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine
ADRA1A protein, human
Adrenergic alpha-Antagonists
Piperazines
Pyrimidinones
Receptors, Adrenergic, alpha-1
Receptors, Opioid, mu
Recombinant Proteins
GTP-Binding Proteins