title: Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
abstract: The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. meena.v.patel@abbott.com
authors.forename: Meena V
authors.initials: MV
authors.lastname: Patel
authors.forename: Teodozyj
authors.initials: T
authors.lastname: Kolasa
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mortell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Hakeem
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rohde
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Nelson
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Loan N
authors.initials: LN
authors.lastname: Miller
authors.forename: Marie E
authors.initials: ME
authors.lastname: Uchic
authors.forename: Marc A
authors.initials: MA
authors.lastname: Terranova
authors.forename: Odile F
authors.initials: OF
authors.lastname: El-Kouhen
authors.forename: Diana L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: Marian T
authors.initials: MT
authors.lastname: Namovic
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hollingsworth
authors.forename: Renjie
authors.initials: R
authors.lastname: Chang
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Martino
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Ruth
authors.initials: R
authors.lastname: Martin
authors.forename: John F
authors.initials: JF
authors.lastname: Darbyshire
authors.forename: Gary
authors.initials: G
authors.lastname: Gintant
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
mesh_terms: D000200:Action Potentials; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D000072237:ERG1 Potassium Channel; D007172:Erectile Dysfunction / Q000188:drug therapy*; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D003497:Cyclic N-Oxides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D050638:Receptors, Dopamine D4; C517239:3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-(2,4'-bipyridine)-1'-ylmethyl)benzamide