The in vivo pharmacological profile of CS‐747, a novel antiplatelet agent with platelet ADP receptor antagonist properties

@article{Sugidachi2000TheIV,
  title={The in vivo pharmacological profile of CS‐747, a novel antiplatelet agent with platelet ADP receptor antagonist properties},
  author={A. Sugidachi and F. Asai and T. Ogawa and T. Inoue and H. Koike},
  journal={British Journal of Pharmacology},
  year={2000},
  volume={129}
}
CS‐747 is a novel antiplatelet agent that generates an active metabolite, R‐99224, in vivo. CS‐747 itself was totally inactive in vitro. This study examined in vivo pharmacological profiles of CS‐747 after single oral administration to rats. Orally administered CS‐747 (0.3–10 mg kg−1) partially but significantly decreased [3H]‐2‐methylthio‐ADP binding to rat platelets. CS‐747 (3 mg kg−1, p.o.) treatment neutralized ADP‐induced decreases of cyclic AMP concentrations induced by prostaglandin E1… Expand
Antiplatelet action of R‐99224, an active metabolite of a novel thienopyridine‐type Gi‐linked P2T antagonist, CS‐747
TLDR
R‐99224 is a selective and irreversible antagonist of Gi‐linked P2T receptors and that R‐99 224 is a responsible molecule for in vivo actions of CS‐747 are suggested. Expand
Identification of the active metabolite of ticlopidine from rat in vitro metabolites
TLDR
Results suggest that UR‐4501 is the molecule responsible for the in vivo activities of ticlopidine, and strongly inhibited ADP‐ and collagen‐ induced aggregation and slightly inhibited thrombin‐induced aggregation. Expand
Interaction of the active metabolite of prasugrel, R‐138727, with cysteine 97 and cysteine 175 of the human P2Y12 receptor
TLDR
The experiments demonstrate a potent and irreversible action of R‐138727 at the recombinant human P2Y12 receptor and suggest that this site of action is close to the ligand‐binding site of the receptor. Expand
The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite
TLDR
The greater in vivo antiplatelet potency of prasug Rel reflects more efficient in vivo generation of its AM, which demonstrates similar in vitro activity to clopidogrel AM. Expand
Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile.
TLDR
Clinical studies in patients with cardiovascular disease confirmed the potent antiplatelet effect of prasugrel compared with clopidogrel and aided in dose selection for the recently completed phase 3 trial of patients with acute coronary syndrome undergoing percutaneous coronary intervention. Expand
W1, a Novel Oral Antiplatelet Agent With Less Resistance Than Clopidogrel
TLDR
Both W1 and CLO showed antiplatelet and antithrombotic effects, while the former exhibited less CLO resistance in combination with omeprazole or amlodipine, 2 drugs that inhibit CLO metabolism. Expand
The reversible P2Y12 antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function
TLDR
Cangrelor influences the ability of the active metabolites of clopidogrel or prasugrel to inhibit platelet function irreversibly, and careful consideration should be given to the timing of administration of an oral P2Y12 antagonist following cangrelor infusion. Expand
A Pharmacodynamic Study of CN-218, a Novel Antiplatelet and Antithrombotic Agent Primarily Targeting the P2Y12 Receptor
TLDR
CN-218 may be a promising antithrombotic agent, with potent antiplatelet and significant anticoagulant activity, as well as a lower risk of bleeding compared to clopidogrel and prasugrel. Expand
Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases
TLDR
The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Expand
Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A single ascending dose study in healthy humans
TLDR
Prasugrel 30 and 75 mg were well tolerated and achieved a consistently high level of platelet inhibition with a fast onset of action, suggesting irreversible inhibition by prasugrel and/or its metabolites. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 46 REFERENCES
Inhibitory effects of TA-993, a new 1,5-benzothiazepine derivative, on platelet aggregation.
TLDR
TA-993 inhibited both primary and secondary phases of ADP-induced platelet aggregation and also exhibited a disaggregating effect on human platelet aggregates, suggesting that antiplatelet action is more characteristic of the l-cis than the d- cis 1,5-benzothiazepine structure and that TA-993 may become a clinically useful antiplatelets agent of this structure series. Expand
Specific inhibition of ADP‐induced platelet aggregation by clopidogrel in vitro
TLDR
It is concluded that clopidogrel specifically inhibits ADP‐induced aggregation of washed platelets in vitro without hepatic bioactivation. Expand
P2Y1‐receptors in human platelets which are pharmacologically distinct from P2YADP‐receptors
TLDR
The results of this study indicate that human washed platelets contain P2Y1‐receptors which mediate increases in [Ca2+]i and that this receptor population is pharmacologically distinct from P2yADP‐receptorors. Expand
Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors
TLDR
The current data strongly suggest the presence of two ADP receptors, one responsible for shape change and rapid Ca2+ influx and the other a Gi protein‐coupled receptor responsible for Ca2- mobilization from internal stores, inhibition of adenylyl cyclase and platelet aggregation. Expand
Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase.
  • D. Mills, R. Puri, +5 authors R. Colman
  • Chemistry, Medicine
  • Arteriosclerosis and thrombosis : a journal of vascular biology
  • 1992
Clopidogrel, like the homologous thienopyridine derivative ticlopidine, selectively inhibits platelet aggregation induced by ADP. We have previously described two nucleotide-binding sites onExpand
The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A.
TLDR
The efficacy of clopidogrel was increased in animals pretreated with 3-methylcholanthrene and beta-naphthoflavone, indicating that the cytochrome P450-1A subfamily pathway was mainly involved in the activating metabolism of clobidog rel, and the use of specific antibodies directed against the various cyto Chrome P450 subfamilies ascertained this observation. Expand
Ticlopidine and clopidogrel (SR 25990C) selectively neutralize ADP inhibition of PGE1-activated platelet adenylate cyclase in rats and rabbits.
TLDR
Ticlopidine and clopidogrel selectively neutralize the ADP inhibition of PGE1-activated platelet adenylate cyclase in rats and rabbits. Expand
Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states.
TLDR
Ticlopidine is an inhibitor of platelet action that has been used in the treatment of a variety of disease states in which platelets play a prominent role but trials of patients with intermittent claudication, angina pectoris, diabetes mellitus with microvascular disease, aortocoronary bypass grafts, and vascular prostheses have had conflicting results or have shown an unfavourable side effect profile. Expand
The roles of prostaglandin endoperoxides, thromboxane A2 and adenosine diphosphate in collagen‐induced aggregation in man and the rat
TLDR
The results with CP/CPK suggest that TxB2 formation is dependent either on the prior release of platelet ADP or on aggregation itself rather than being responsible for the aggregation response. Expand
ADP plays a key role in thrombogenesis in rats.
TLDR
Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency, and ticlopidine and PCR 4099 were very potent antithrombotics in all the models. Expand
...
1
2
3
4
5
...