Another drug onto the market this month is Pazopanib, marketed as Votrient, which was approved on October 19th. Pazopanib Hydrochloride (previously known as GW-786034-B) is the sixth drug to be approved for kidney cancer, after Sorafenib (trade name Nexavar), Sunitinib (trade name Sutent), Temsirolimus (trade name Torisel), Everolimus (trade name Afinitor) and Bevacizumab (trade name Avastin). Sorafenib and Sunitinib are both orally dosed small molecule inhibitors of tyrosine protein kinases, which interfere with tumor growth by inhibiting angiogenesis as well as tumor cell proliferation; Temsirolimus and Everolimus are specific inhibitors of mTOR (mammalian target of rapamycin), a serine-threonine kinase, which interfere with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells; Bevacizumab is a monoclonal antibody that recognizes and blocks VEGF, which is a chemical signal that stimulates angiogenesis. Pazopanib is a small-molecule drug (Molecular Weight is 437.5 g.mol-1 for Pazopanib itself and 474.0 g.mol-1 for the HCl salt), fully Rule-of-Five compliant, lipophilic and practically insoluble in aqueous media. It is orally absorbed, has a high plasma protein binding of >99% and is metabolized by CYP3A4 (and therefore has many drug-drug interactions with substrates, inhibitors and inducers of CYP3A4) with minor contribution from CYP1A2 and CYP2C8. Pazopanib has a mean half-life of 30.9 hours and elimination is primarily through feces (>96% of dose). The recommended dosage is 800mg once daily (equivalent to ca 1.8 mmol). Among one of the potential adverse events is the propensity for the compound to increase QT interval. Full prescribing information can be found here. Pazopanib has a boxed warning. The structure 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide. Pazopanib is largely planar and and mimics the adenine ring of the enzyme cofactor ATP. Of additional note is the presence of an aryl-sulphonamide (in the bottom left of the image) - these are often weakly acidic.
<NAME="Pazopanib"> <SMILES="O=S(=O)(N)c1c(ccc(c1)Nc2nccc(n2)N(c4ccc3c(nn(c3C)C)c4)C)C"> <InChI="InChI=1/C21H23N7O2S.ClH/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16;/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25);1H" > <InChIKey="MQHIQUBXFFAOMK-UHFFFAOYAU"> <ChemDraw=Pazopanib.cdx>The manufacturer of Pazopanib is GlaxoSmithKline and the product website is www.votrient.com.