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.

Comments

ChEMBL 34 is out!

We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains: 2,431,025 compounds (of which 2,409,270 have mol files) 3,106,257 compound records (non-unique compounds) 20,772,701 activities 1,644,390 assays 15,598 targets 89,892 documents Data can be downloaded from the ChEMBL FTP site: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.

New SureChEMBL announcement

(Generated with DALL-E 3 ∙ 30 October 2023 at 1:48 pm) We have some very exciting news to report: the new SureChEMBL is now available! Hooray! What is SureChEMBL, you may ask. Good question! In our portfolio of chemical biology services, alongside our established database of bioactivity data for drug-like molecules ChEMBL , our dictionary of annotated small molecule entities ChEBI , and our compound cross-referencing system UniChem , we also deliver a database of annotated patents! Almost 10 years ago , EMBL-EBI acquired the SureChem system of chemically annotated patents and made this freely accessible in the public domain as SureChEMBL. Since then, our team has continued to maintain and deliver SureChEMBL. However, this has become increasingly challenging due to the complexities of the underlying codebase. We were awarded a Wellcome Trust grant in 2021 to completely overhaul SureChEMBL, with a new UI, backend infrastructure, and new f

Accessing SureChEMBL data in bulk

It is the peak of the summer (at least in this hemisphere) and many of our readers/users will be on holiday, perhaps on an island enjoying the sea. Luckily, for the rest of us there is still the 'sea' of SureChEMBL data that awaits to be enjoyed and explored for hidden 'treasures' (let me know if I pushed this analogy too far). See here and here for a reminder of SureChEMBL is and what it does. This wealth of (big) data can be accessed via the SureChEMBL interface , where users can submit quite sophisticated and granular queries by combining: i) Lucene fields against full-text and bibliographic metadata and ii) advanced structure query features against the annotated compound corpus. Examples of such queries will be the topic of a future post. Once the search results are back, users can browse through and export the chemistry from the patent(s) of interest. In addition to this functionality, we've been receiving user requests for local (behind the

New Drug Approvals - Pt. XVII - Telavancin (Vibativ)

The latest new drug approval, on 11th September 2009 was Telavancin - which was approved for the treatment of adults with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria , including Staphylococcus aureus , both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains. Telavancin is also active against Streptococcus pyogenes , Streptococcus agalactiae , Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus ) and Enterococcus faecalis (vancomycin susceptible isolates only). Telavancin is a semisynthetic derivative of Vancomycin. Vancomycin itself is a natural product drug, isolated originally from soil samples in Borneo, and is produced by controlled fermentation of Amycolatopsis orientalis - a member of the Actinobacteria . Telavancin has a dual mechanism of action, firstly it inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptid

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

The ChEMBL-og

Search This Blog