title: Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.
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.
authors.affiliation: Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lagu
authors.forename: D
authors.initials: D
authors.lastname: Tian
authors.forename: D
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: M R
authors.initials: MR
authors.lastname: Marzabadi
authors.forename: W C
authors.initials: WC
authors.lastname: Wong
authors.forename: S W
authors.initials: SW
authors.lastname: Miao
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.forename: G
authors.initials: G
authors.lastname: Chiu
authors.forename: J
authors.initials: J
authors.lastname: Fang
authors.forename: C
authors.initials: C
authors.lastname: Forray
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: R W
authors.initials: RW
authors.lastname: Ransom
authors.forename: T B
authors.initials: TB
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: O'Malley
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
authors.forename: C
authors.initials: C
authors.lastname: Gluchowski
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D019204:GTP-Binding Proteins / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C401324:1,2,3,6-tetrahydro-1-(N-((4-(2-nitrophenyl)piperazin-1-yl)propyl)carboxamido)-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine; C547713:ADRA1A protein, human; D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011744:Pyrimidinones; D018340:Receptors, Adrenergic, alpha-1; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D019204:GTP-Binding Proteins