Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist.
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.
Bondinell
W E
WE
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Keenan
R M
RM
Miller
W H
WH
Ali
F E
FE
Allen
A C
AC
de Brosse
C W
CW
Eggleston
D S
DS
Erhard
K F
KF
Haltiwanger
R C
RC
Huffman
W F
WF
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
D001570:Benzodiazepinones; D010455:Peptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C093094:SB 208651; C086543:SK&F 107260