title: N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
abstract: Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
authors.affiliation: Roche Bioscience, Palo Alto, California 94304-1397, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Elworthy
authors.forename: A P
authors.initials: AP
authors.lastname: Ford
authors.forename: G W
authors.initials: GW
authors.lastname: Bantle
authors.forename: D J
authors.initials: DJ
authors.lastname: Morgans
authors.forename: R S
authors.initials: RS
authors.lastname: Ozer
authors.forename: W S
authors.initials: WS
authors.lastname: Palmer
authors.forename: D B
authors.initials: DB
authors.lastname: Repke
authors.forename: M
authors.initials: M
authors.lastname: Romero
authors.forename: L
authors.initials: L
authors.lastname: Sandoval
authors.forename: E B
authors.initials: EB
authors.lastname: Sjogren
authors.forename: F X
authors.initials: FX
authors.lastname: Talamás
authors.forename: A
authors.initials: A
authors.lastname: Vazquez
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.forename: N F
authors.initials: NF
authors.lastname: Arredondo
authors.forename: D R
authors.initials: DR
authors.lastname: Blue
authors.forename: A
authors.initials: A
authors.lastname: DeSousa
authors.forename: L M
authors.initials: LM
authors.lastname: Gross
authors.forename: M S
authors.initials: MS
authors.lastname: Kava
authors.forename: J D
authors.initials: JD
authors.lastname: Lesnick
authors.forename: R L
authors.initials: RL
authors.lastname: Vimont
authors.forename: T J
authors.initials: TJ
authors.lastname: Williams
authors.forename: Q M
authors.initials: QM
authors.lastname: Zhu
authors.forename: J R
authors.initials: JR
authors.lastname: Pfister
authors.forename: D E
authors.initials: DE
authors.lastname: Clarke
mesh_terms: D000293:Adolescent; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001667:Binding, Competitive; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011224:Prazosin / Q000378:metabolism; D011437:Propylamines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000577:Amides; D010879:Piperazines; D011437:Propylamines; D011224:Prazosin