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New Drug Approvals - Pt. V - Everolimus (Afinitor)

Also approved this year, on March 30th 2009, is Everolimus (USAN). Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, and is indicated for the treatment of advanced renal cell carcinoma after failure of treatment with Sunitinib or Sorafenib. Sunitinib and Sorafenib are both orally dosed small molecule inhibitors of protein kinases. Everolimus is also marketed under the trade name (although not currently in the US) as Certican, which is used for immunosuppression in transplant therapy. Everolimus (previously known by the research code RAD-001) is a relatively large 'small molecule' drug (Molecular Weight of 958.2 g.mol-1), lipophilic, orally absorbed and has a low plasma binding of ~74%. Everolimus is primarily metabolized CYP3A4 routes, with known metabolites being essentially inactive as mTor inhibitors, these are largely excreted in the feces. Everolimus has a long mean elimination half-life of ~30 hours. Typical dosage is 10 mg (equivalent to ca. 10.4 umol) once a day. The full prescribing information can be found here.

The structure (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone) contains a macrolide ring (a large macrocyclic ester), often a characteristic of natural products. In fact, with the complex size, high number of defined stereocenters Everolimus is very 'natural product like'. of striking functional group interest is the presence of the unusual alpha-keto amide functionality (the two adjacent carbonyls and the amide from the six membered piperidine ring - this has unusual conformational and reactivity properties, and is associated with the conformation required for cis- to trans-isomerisation for a proline containing peptide.

Everolimus is chemcially very similar to the natural product drug Rapamycin (in fact one chemical name for Everolimus is 42-O-(2-hydroxyethyl)-Rapamycin). Confusingly Rapamycin is also known by the USAN Sirolimus. Sirolimus was originally identified as an active component of a soil isolate from Easter Island, eventually the source of this molecule was found to be the bacteria Streptomyces hygroscopicus. A further member of the family is the drug Tacrolimus (USAN) (also know by the research code FK-506) which was isolated from a Japanese soil sample, and is made by the bacteria Streptomyces tsukubaensis. Rather excitingly drugs of this class have been very recently shown to extend the lifespan of mice (click here for a pdf of the Nature paper, and here for further media coverage). Of course, due to the other functions of Rapamycin (suppression of the immune system) drugs of this class may not actually be that useful for the extension of life.

Everolimus canonical SMILES: O=C2[C@H](C)C[C@@H](\C=C\C=C/C=C(\C)[C@@H](OC)C[C@H]4O[C@@](O)(C(=O)C(=O)N3[C@H](C(=O)O[C@H]([C@H](C)C[C@@H]1CC[C@@H](OCCO)[C@H](OC)C1)CC(=O)[C@@H](/C=C(/C)[C@@H](O)[C@H]2OC)C)CCCC3)[C@@H](CC4)C)C Everolimus InChI: InChI=1/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19- 38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35( 4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6) 48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43 -46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11-,16-12+,33- 17+,37-27-/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,4 9+,53-/m1/s1 Everolimus InChIKey: HKVAMNSJSFKALM-CNPAPGRKBU Everolimus CAS registry: 159351-69-6 Everolimus ChemDraw: Everolimus.cdx

The manufacturer of Everolimus is Novartis and the product website is www.afinitor.com.

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