title: Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist.
abstract: The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4- (aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo- 4- (2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, (3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SK&F 107260 (2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10%. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
authors.forename: W E
authors.initials: WE
authors.lastname: Bondinell
authors.forename: R M
authors.initials: RM
authors.lastname: Keenan
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: F E
authors.initials: FE
authors.lastname: Ali
authors.forename: A C
authors.initials: AC
authors.lastname: Allen
authors.forename: C W
authors.initials: CW
authors.lastname: de Brosse
authors.forename: D S
authors.initials: DS
authors.lastname: Eggleston
authors.forename: K F
authors.initials: KF
authors.lastname: Erhard
authors.forename: R C
authors.initials: RC
authors.lastname: Haltiwanger
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D001792:Blood Platelets / Q000737:chemistry* / Q000648:ultrastructure; D004285:Dogs; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008297:Male; D008745:Methylation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits
chemical_list: D001570:Benzodiazepinones; D010455:Peptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C093094:SB 208651; C086543:SK&F 107260