title: Pharmacology of ABT-491, a highly potent platelet-activating factor receptor antagonist.
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.
authors.affiliation: Immunoscience Research Area, Department 47J, Abbott Laboratories, Abbott Park, IL, USA. dan.h.albert@abbott.com
authors.forename: D H
authors.initials: DH
authors.lastname: Albert
authors.forename: T J
authors.initials: TJ
authors.lastname: Magoc
authors.forename: P
authors.initials: P
authors.lastname: Tapang
authors.forename: G
authors.initials: G
authors.lastname: Luo
authors.forename: D W
authors.initials: DW
authors.lastname: Morgan
authors.forename: M
authors.initials: M
authors.lastname: Curtin
authors.forename: G S
authors.initials: GS
authors.lastname: Sheppard
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: H R
authors.initials: HR
authors.lastname: Heyman
authors.forename: S K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000208:Acute Disease; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009504:Neutrophils / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012769:Shock / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C107116:ABT 491