Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.
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.
Lagu
B
B
Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.
Tian
D
D
Nagarathnam
D
D
Marzabadi
M R
MR
Wong
W C
WC
Miao
S W
SW
Zhang
F
F
Sun
W
W
Chiu
G
G
Fang
J
J
Forray
C
C
Chang
R S
RS
Ransom
R W
RW
Chen
T B
TB
O'Malley
S
S
Zhang
K
K
Vyas
K P
KP
Gluchowski
C
C
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
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