Abstract |
ABT-491 (4-ethynyl-N, N-dimethyl-3-[3-fluoro-4-[(2-methyl-1H-imidazo-[4,5-c]pyridin-1-yl)methy l]benzoyl]-1H- indole-1-carboxamide hydrochloride) is a novel PAF ( platelet-activating factor) receptor antagonist with a K(i) for inhibiting PAF binding to human platelets of 0.6 nM. Binding kinetics of ABT-491 to the PAF receptor is consistent with a relatively slow off-rate of the antagonist when compared to PAF. Inhibition of PAF binding is selective and is correlated with functional antagonism of PAF-mediated cellular responses (Ca2+ mobilization, priming, and degranulation). Administration of ABT-491 in vivo leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension, and edema) and PAF-induced lethality. Oral potency (ED50) was between 0.03 and 0.4 mg/kg in rat, mouse, and guinea-pig. When administered intravenously in these species, ABT-491 exhibited ED50 values between 0.005 and 0.016 mg/kg. An oral dose of 0.5 mg/kg in rat provided > 50% protection for 8 h against cutaneous PAF challenge. ABT-491 administered orally was also effective in inhibiting lipopolysaccharide- induced hypotension (ED50 = 0.04 mg/kg), gastrointestinal damage (0.05 mg/kg, 79% inhibition), and lethality (1 mg/kg, 85% vs. 57% survival). The potency of this novel antagonist suggests that ABT-491 will be useful in the treatment of PAF-mediated diseases.
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Authors | D H Albert, T J Magoc, P Tapang, G Luo, D W Morgan, M Curtin, G S Sheppard, L Xu, H R Heyman, S K Davidsen, J B Summers, G W Carter |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 325
Issue 1
Pg. 69-80
(Apr 23 1997)
ISSN: 0014-2999 [Print] Netherlands |
PMID | 9151941
(Publication Type: Journal Article)
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Chemical References |
- Imidazoles
- Indoles
- Lipopolysaccharides
- Platelet Activating Factor
- Platelet Membrane Glycoproteins
- Receptors, Cell Surface
- Receptors, G-Protein-Coupled
- platelet activating factor receptor
- ABT 491
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Topics |
- Acute Disease
- Animals
- Blood Platelets
(drug effects)
- Dose-Response Relationship, Drug
- Endotoxemia
(drug therapy)
- Guinea Pigs
- Humans
- Imidazoles
(pharmacology)
- Indoles
(pharmacology)
- Inflammation
(chemically induced, drug therapy)
- Lipopolysaccharides
(toxicity)
- Male
- Mice
- Mice, Inbred ICR
- Neutrophils
(drug effects)
- Platelet Activating Factor
(antagonists & inhibitors, drug effects, metabolism)
- Platelet Membrane Glycoproteins
(antagonists & inhibitors, metabolism)
- Rabbits
- Rats
- Receptors, Cell Surface
- Receptors, G-Protein-Coupled
- Shock
(chemically induced, drug therapy)
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