Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists

M L Curtin; S K Davidsen; H R Heyman; R B Garland; G S Sheppard; A S Florjancic; L Xu; G M Carrera Jr; D H Steinman; J A Trautmann; D H Albert; T J Magoc; P Tapang; D A Rhein; R G Conway; G Luo; J F Denissen; K C Marsh; D W Morgan; J B Summers

doi:10.1021/jm970389+

Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists

J Med Chem. 1998 Jan 1;41(1):74-95. doi: 10.1021/jm970389+.

Affiliation

¹ Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. mike.curtin@abbott.com

PMID: 9438024
DOI: 10.1021/jm970389+

Abstract

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.

MeSH terms

Animals
Biological Availability
Blood Platelets / drug effects
Blood Platelets / physiology
Capillary Permeability / drug effects
Dogs
Female
Guinea Pigs
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
Macaca fascicularis
Male
Molecular Structure
Platelet Activating Factor / antagonists & inhibitors*
Platelet Activating Factor / pharmacology
Platelet Aggregation Inhibitors / chemical synthesis*
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacokinetics
Platelet Aggregation Inhibitors / pharmacology
Platelet Membrane Glycoproteins / metabolism*
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacokinetics
Pyridines / pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Cell Surface*
Receptors, G-Protein-Coupled*
Structure-Activity Relationship

Substances

Imidazoles
Platelet Activating Factor
Platelet Aggregation Inhibitors
Platelet Membrane Glycoproteins
Pyridines
Receptors, Cell Surface
Receptors, G-Protein-Coupled
platelet activating factor receptor