title: Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
abstract: Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
authors.affiliation: Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: S W
authors.initials: SW
authors.lastname: Miao
authors.forename: B
authors.initials: B
authors.lastname: Lagu
authors.forename: G
authors.initials: G
authors.lastname: Chiu
authors.forename: J
authors.initials: J
authors.lastname: Fang
authors.forename: T G
authors.initials: TG
authors.lastname: Murali Dhar
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Tyagarajan
authors.forename: M R
authors.initials: MR
authors.lastname: Marzabadi
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: W C
authors.initials: WC
authors.lastname: Wong
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.forename: D
authors.initials: D
authors.lastname: Tian
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: R W
authors.initials: RW
authors.lastname: Ransom
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: P
authors.initials: P
authors.lastname: Kling
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
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011467:Prostate / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013237:Stereoisomerism; D014521:Urethra / Q000187:drug effects / Q000502:physiology
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D011744:Pyrimidinones; D018340:Receptors, Adrenergic, alpha-1; C401321:SNAP 6201