title: Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety.
abstract: We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.
authors.affiliation: Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Murali Dhar
authors.forename: D
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: M R
authors.initials: MR
authors.lastname: Marzabadi
authors.forename: B
authors.initials: B
authors.lastname: Lagu
authors.forename: W C
authors.initials: WC
authors.lastname: Wong
authors.forename: G
authors.initials: G
authors.lastname: Chiu
authors.forename: S
authors.initials: S
authors.lastname: Tyagarajan
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: D
authors.initials: D
authors.lastname: Tian
authors.forename: Q
authors.initials: Q
authors.lastname: Shen
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: J M
authors.initials: JM
authors.lastname: Wetzel
authors.forename: C
authors.initials: C
authors.lastname: Forray
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: T P
authors.initials: TP
authors.lastname: Broten
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: T B
authors.initials: TB
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: O'Malley
authors.forename: R
authors.initials: R
authors.lastname: Ransom
authors.forename: K
authors.initials: K
authors.lastname: Schneck
authors.forename: R
authors.initials: R
authors.lastname: Bendesky
authors.forename: C M
authors.initials: CM
authors.lastname: Harrell
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019204:GTP-Binding Proteins / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010880:Piperidines / 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; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014521:Urethra / Q000187:drug effects / Q000502:physiology
chemical_list: C401323:1-(N-(3-(4-methyl-4-phenylpiperidin-1-yl)propyl)carboxamido)-6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine; C401322:5-carboxamido-1-(N-(3-(4-cyano-4-phenylpiperidin-1-yl)propyl)carboxamido)-6-(2,4-difluorophenyl)-4-ethyl-2-oxo-1,2,3,6-tetrahydropyrimidine; C547713:ADRA1A protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010880:Piperidines; D011744:Pyrimidinones; D018340:Receptors, Adrenergic, alpha-1; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; C032727:piperidine; D019204:GTP-Binding Proteins