Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists.
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.
Curtin
M L
ML
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. mike.curtin@abbott.com
Davidsen
S K
SK
Heyman
H R
HR
Garland
R B
RB
Sheppard
G S
GS
Florjancic
A S
AS
Xu
L
L
Carrera
G M
GM
Steinman
D H
DH
Trautmann
J A
JA
Albert
D H
DH
Magoc
T J
TJ
Tapang
P
P
Rhein
D A
DA
Conway
R G
RG
Luo
G
G
Denissen
J F
JF
Marsh
K C
KC
Morgan
D W
DW
Summers
J B
JB
D000818:Animals; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship
D007093:Imidazoles; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor