title: In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.
abstract: alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.
authors.affiliation: Departments of Medicinal Chemistry, Pharmacology, and Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Barrow
authors.forename: P G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: H G
authors.initials: HG
authors.lastname: Selnick
authors.forename: K L
authors.initials: KL
authors.lastname: Glass
authors.forename: K E
authors.initials: KE
authors.lastname: Rittle
authors.forename: K F
authors.initials: KF
authors.lastname: Gilbert
authors.forename: T G
authors.initials: TG
authors.lastname: Steele
authors.forename: C F
authors.initials: CF
authors.lastname: Homnick
authors.forename: R M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: R W
authors.initials: RW
authors.lastname: Ransom
authors.forename: P
authors.initials: P
authors.lastname: Kling
authors.forename: D
authors.initials: D
authors.lastname: Reiss
authors.forename: T P
authors.initials: TP
authors.lastname: Broten
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: S S
authors.initials: SS
authors.lastname: O'Malley
authors.forename: T V
authors.initials: TV
authors.lastname: Olah
authors.forename: J D
authors.initials: JD
authors.lastname: Ellis
authors.forename: A
authors.initials: A
authors.lastname: Barrish
authors.forename: K
authors.initials: K
authors.lastname: Kassahun
authors.forename: P
authors.initials: P
authors.lastname: Leppert
authors.forename: D
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: C
authors.initials: C
authors.lastname: Forray
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D008297:Male; D011470:Prostatic Hyperplasia / Q000188:drug therapy; 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 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C411461:4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3-(4-(4-fluorophenyl)piperidin-1-yl)propyl)amide; D000317:Adrenergic alpha-Antagonists; D011744:Pyrimidinones; D018340:Receptors, Adrenergic, alpha-1