Non-peptide GPIIb/IIIa inhibitors. 20. Centrally constrained thienothiophene alpha-sulfonamides are potent, long acting in vivo inhibitors of platelet aggregation.
The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of 4 to resting platelets is a diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) and that 4 binds to dog and human platelets with comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 microg/kg [corrected], and an oral dose of 50-90 microg/kg [corrected] followed by low daily doses of 10 microg/kg [corrected] was sufficient to maintain approximately 80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 +/- 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.
Egbertson
M S
MS
Departments of Medicinal Chemistry and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Cook
J J
JJ
Bednar
B
B
Prugh
J D
JD
Bednar
R A
RA
Gaul
S L
SL
Gould
R J
RJ
Hartman
G D
GD
Homnick
C F
CF
Holahan
M A
MA
Libby
L A
LA
Lynch
J J
JJ
Lynch
R J
RJ
Sitko
G R
GR
Stranieri
M T
MT
Vassallo
L M
LM
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C120072:2-(N-(3-pyridylsulfonyl)amino)-3-((2-carbonyl-5-(2-(piperidin-4-yl)ethyl)thieno(2,3-b)thiopheneyl)amino)propionic acid; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D013876:Thiophenes