title: Non-peptide glycoprotein IIb/IIIa inhibitors. 17. Design and synthesis of orally active, long-acting non-peptide fibrinogen receptor antagonists.
abstract: The synthesis and pharmacological evaluation of 5 (L-738, 167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be > 33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by > 85% 24 h after the oral administration of 5 to dogs at 100 micrograms/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
authors.affiliation: Merck Research Laboratories, Department of Medicinal Chemistry, West point, Pennsylvania 19486, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Askew
authors.forename: R A
authors.initials: RA
authors.lastname: Bednar
authors.forename: B
authors.initials: B
authors.lastname: Bednar
authors.forename: D A
authors.initials: DA
authors.lastname: Claremon
authors.forename: J J
authors.initials: JJ
authors.lastname: Cook
authors.forename: C J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: C A
authors.initials: CA
authors.lastname: Hunt
authors.forename: R J
authors.initials: RJ
authors.lastname: Gould
authors.forename: R J
authors.initials: RJ
authors.lastname: Lynch
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: S L
authors.initials: SL
authors.lastname: Gaul
authors.forename: M T
authors.initials: MT
authors.lastname: Stranieri
authors.forename: G R
authors.initials: GR
authors.lastname: Sitko
authors.forename: M A
authors.initials: MA
authors.lastname: Holahan
authors.forename: J D
authors.initials: JD
authors.lastname: Glass
authors.forename: T
authors.initials: T
authors.lastname: Hamill
authors.forename: L M
authors.initials: LM
authors.lastname: Gorham
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: J J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D019096:Vitronectin / Q000378:metabolism
chemical_list: D001381:Azepines; D005343:Fibrinolytic Agents; D005353:Fibronectins; C105929:L 738167; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D019096:Vitronectin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen