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The SARfaris: GPCR, Kinase, ADME

Wednesday, 15 July 2009

New Drug Approvals - Pt. XI - Prasugrel Hydrochloride (Effient)

The latest approval this year is Prasugrel (USAN), approved on July 10th under the trade name Effient. Prasugrel is a P2Y12 receptor platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention. Prasugrel is the third to market in the thienopyridine class of ADP receptors antagonists, after Ticlopidine (trade name Ticlid) and Clopidogrel (trade name Plavix). Prasugrel is a prodrug; meaning that Prasugrel is not therapeutically active itself, but is metabolized in the body to give the pharmacologically active metabolite. Additionally, the metabolically activated form of Prasugrel irreversibly binds to its receptor - this means that it forms an unbreakable chemical bond to its target, again this is quite an unusual feature.

Prasugrel is a small molecule drug (Molecular Weight of 343.4 g.mol-1 for Prasugrel itself and 409.9 g.mol-1 for the HCl salt), is fully Rule-of-Five compliant, lipophilic and insoluble in water. Prasugrel has a good oral absorption (≥79% absorbed), an elimination half-life of ~7 hours (for the active metabolite, see below) and a high plasma protein binding of 98%. The activation of Prasugrel is rapid and complex, being first metabolized first to a thiolactone, which is then converted to the active metabolite, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. CYP2B6 is quite an unusual cytochrome p450 to be involved in drug metabolism. Prasugrel's active metabolite has an apparent volume of distribution of 44-68 L and an apparent clearance of 112-166 L/h. Prasugrel's excretion is mostly renal (68%), being excreted as inactive metabolites. Recommended dosage is initially a 60 mg once a day 'loading dose', continuing at 10 mg once daily, in combination with 75-325 mg of aspirin. Full prescribing information can be found here.

Prasugrel has a boxed warning (colloquially know as 'black box').

The chemical structure is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. The molecule contains a piperidine ring fused with a thiophene ring (the common feature between to the thienopyridine class of ADP receptors). It also contains a racemic center adjacent to the piperidine nitrogen. Since the drug is racemic, the stereoisomers have different pharmacological activity and different metabolic properties. The remainder of the molecule is quite rigid, with few rotational bonds.

Prasugrel canonical SMILES: Fc1ccccc1C(N3Cc2c(sc(OC(=O)C)c2)CC3)C(=O)C4CC4 Prasugrel InChI: InChI=1/C20H20FNO3S/c1-12(23)25-18-10-14-11-22(9-8-17(14)26-18)19 (20(24)13-6-7-13)15-4-2-3-5-16(15)21/h2-5,10,13,19H,6-9,11H2,1H3 Prasugrel InChIKey: DTGLZDAWLRGWQN-UHFFFAOYAR Prasugrel CAS registry: 150322-43-3 Prasugrel ChemDraw: Prasugrel.cdx

The product is marketed by Eli Lilly and Company and Daiichi Sankyo, Inc. and manufactured by Eli Lilly and Company. The product website is

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