The in vivo and in vitro activity of AHR-13268D, a new antiallergic/antihistaminic agent.
AHR-13268D (4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1- piperidinyl]propoxy]benzoic acid, sodium salt) is a potent, long-acting water soluble, antiallergic and antihistaminic agent. AHR-13268D protects sensitive guinea pigs from collapse induced by aerosolized antigen; 1, 5, and 24 h ED50s in the test were 0.27, 0.25, 0.93 mg/kg, PO, respectively. AHR-13268D was also active when given as an aerosol, the 1 h ED50 = 0.29%. In the rat passivefoot anaphylaxis test. AHR-13268D was slightly more active (1.55 times) than AHR-5333B when given orally 1 h prior to challenge and equipotent to cromolyn when given intravenously immediately prior to challenge. AHR-13268D displayed potent, long-acting antihistaminic activity in naive guinea pigs; the 1, 5, and 24 h oral ED50s being in the range of 0.3 mg/kg. AHR-13268D (10 to 20 mg/kg, PO) attenuated the skin responses to ascaris antigen in sensitive dogs and did not alter the EEG pattern or sleep/wake patterns of cats at doses in vast excess of its antihistaminic activity. In vitro, AHR-13268D was a potent inhibitor of histamine release from rat peritoneal mast cells (IC50 = 0.51 nM) and was as potent as the reference 5-LO inhibitor phenidone in inhibiting antigen-induced contractions of guinea pig ileum in the presence of pyrilamine, atropine, and imidazole (IC50 approximately 300 microM). AHR-13268B was bioavailable (approximately 88%) from capsules or from oral solutions.
Nolan
J C
JC
Department of Pharmacology, A.H. Robins Company, Richmond, VA 23261.
Foxwell
M H
MH
Whitman
L L
LL
Johnson
D N
DN
Yanni
J M
JM
Greene
S V
SV
D000336:Aerosols; D000707:Anaphylaxis / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D000941:Antigens; D001200:Ascaris / Q000276:immunology; D001565:Benzoates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D004569:Electroencephalography; D005260:Female; D005512:Food Hypersensitivity; D006168:Guinea Pigs; D006632:Histamine / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006967:Hypersensitivity / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D007073:Immunoglobulin E / Q000276:immunology; D008168:Lung / Q000503:physiopathology; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012882:Skin Tests
D000336:Aerosols; D000941:Antigens; D001565:Benzoates; D006634:Histamine H1 Antagonists; D010880:Piperidines; C068205:AHR 13268D; D007073:Immunoglobulin E; D006632:Histamine