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.
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.
Patel
Meena V
MV
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. meena.v.patel@abbott.com
Kolasa
Teodozyj
T
Mortell
Kathleen
K
Matulenko
Mark A
MA
Hakeem
Ahmed A
AA
Rohde
Jeffrey J
JJ
Nelson
Sherry L
SL
Cowart
Marlon D
MD
Nakane
Masaki
M
Miller
Loan N
LN
Uchic
Marie E
ME
Terranova
Marc A
MA
El-Kouhen
Odile F
OF
Donnelly-Roberts
Diana L
DL
Namovic
Marian T
MT
Hollingsworth
Peter R
PR
Chang
Renjie
R
Martino
Brenda R
BR
Wetter
Jill M
JM
Marsh
Kennan C
KC
Martin
Ruth
R
Darbyshire
John F
JF
Gintant
Gary
G
Hsieh
Gin C
GC
Moreland
Robert B
RB
Sullivan
James P
JP
Brioni
Jorge D
JD
Stewart
Andrew O
AO
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
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