Ryo Iwamura

Antiplatelet action of R-99224, an active metabolite of a novel thienopyridine-type Gi-linked P2T antagonist, CS-747

CS‐747 is a novel thienopyridine‐type platelet ADP inhibitor which lacks in vitro activity. This study examined pharmacological profiles of R‐99224, a hepatic metabolite of CS‐747. R‐99224 produced a concentration‐dependent inhibition of in vitro platelet aggregation in washed human platelets (0.03 – 1 μg ml−1), which was relatively specific to ADP compared to collagen and thrombin. R‐99224 (0.1 – 3 μg ml−1) also elicited a similar inhibition of ADP‐induced aggregation in rat platelets. The inhibition by R‐99224 (10 μg ml−1) persisted even after platelets were washed three times. Intravenous injection of R‐99224 (0.1 – 3 mg kg−1) to rats resulted in a dose‐dependent inhibition of ex vivo ADP‐induced platelet aggregation. R‐99224 (0.1 – 100 μM) decreased binding of [3H]‐2‐methylthio‐ADP ([3H]‐2‐MeS‐ADP), a stable ligand for platelet ADP receptors, to washed human platelets. The inhibition by R‐99224 reached a plateau at a concentration of 3 μM (1.4 μg ml−1), but complete inhibition was not achieved even at the highest concentration used (100 μM). R‐99224 (10 μM) in combination with ARL‐66096 (0.3 μM), an ATP analogue‐type Gi‐linked P2T receptor antagonist, produced no additional inhibition of [3H]‐2‐MeS‐ADP binding. In contrast, [3H]‐2‐MeS‐ADP binding was completely abolished by R‐99224 (10 μM) in combination with A3P5PS (300 μM), a selective P2Y1 antagonist, suggesting that R‐99224 selectively binds to the Gi‐linked P2T receptor. R‐99224 (0.01 – 3 μg ml−1) inhibited ADP‐induced [125I]‐fibrinogen binding to human platelets in a concentration‐dependent manner. R‐99224 (0.1 – 1 μg ml−1) also inhibited the ADP‐induced decrease in cyclic AMP levels in PGE1‐stimulated platelets, whereas the agent did not affect ADP (10 μM)‐induced Ca2+ mobilization. These findings suggest that R‐99224 is a selective and irreversible antagonist of Gi‐linked P2T receptors and that R‐99224 is a responsible molecule for in vivo actions of CS‐747.

Efficacy of CS‐747, a new potent antiplatelet agent

Clinical Pharmacology & Therapeutics (1999) 65, 148–148; doi:

Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl

EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.

Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent

Purpose The objective of this study was to investigate the pharmacologic characteristics of omidenepag isopropyl (OMDI), a compound developed as a novel intraocular pressure (IOP)-lowering agent, with better IOP control and fewer side effects than other prostanoid receptor agonists such as prostaglandin F receptor (FP) agonists. Methods Binding activities of OMDI and its hydrolyzed form, omidenepag (OMD), to human recombinant prostanoid receptors (DP1-2, EP1-4, FP, and IP) were evaluated. Based on these binding assays, the agonistic activities of OMDI and OMD were further evaluated using cultured cells expressing selected prostanoid receptors. The pharmacokinetics of OMDI after topical administration was assessed in rabbits by measurement of the concentrations of both OMDI and OMD in aqueous humor. The ocular hypotensive effect of OMDI was evaluated in ocular normotensive rabbits, dogs, and both ocular normotensive and hypertensive monkeys. Results OMD was determined to be a selective EP2 receptor agonist. OMDI weakly bound to EP1; however, the agonistic activity of OMDI to this receptor was not demonstrated in the functional assay. After topical administration of OMDI, OMD was detected in aqueous humor whereas OMDI was not detectable. OMDI significantly lowered IOP in both ocular normotensive and hypertensive animals. The significant ocular hypotensive effects of OMDI were demonstrated by both single and repeated dosing, and its effective duration suggests sufficient efficacy by once-daily dosing. Conclusions These studies demonstrated that OMDI is hydrolyzed in the eye to OMD, an EP2 receptor agonist, with a significant ocular hypotensive effect in both ocular normotensive and hypertensive animal models.