2010 New Drug Approvals - Pt. XIV - Dabigatran etexilate (Pradaxa)

ATC Code: B01AE07

Dabigatran etexilate has been approved by the FDA on October 19th 2010. Dabigatran etexilate (also known as BIBR-1048 for Dabigatran etexilate and BIBR-953 for Dabigatran) is approved for the treatment of patients with atrial fibrillation at risk of embolism or stroke. Dabigatran etexilate is a first-in-class (for the US) oral drug preventing blood clotting and stroke by direct inhibition of thrombin and is marketed under the trade name Pradaxa in Europe and the US, and Pradax in certain other territories. In Europe, an earlier oral direct thrombin inhibitor Xemelagatran (trademark:Exanta trademark:Exarta also known as H376/95) was approved, but subsequently was withdrawn due to commercial and perceived safety issues.

The formation of blood clots in the circulation can cause embolism or stroke (or CVA) if other risk factors are present. Depending on the number of risk factors, the risk of suffering a stroke increases up to 7-fold in patients with atrial fibrillation. Patients with atrial fibrillation are therefore often treated with the anticoagulant warfarin (ChEMBL: 494165) to prevent the formation of blood clots, Warfarin is a drug with a poor therapeutic index, and also shows substantial intra-patient variability due to underlying genetic differences, with subsequent required regular patient monitoring.

Dabigatran etexilate is converted to the active drug Dabigatran. It inhibits blood clotting through direct inhibition of thrombin (Uniprot: P00734) and has a larger therapeutic window than warfarin (which is an irreversible inhibitor of vitamin K epoxide reductase). Thrombin is a key serine protease in the blood clotting cascade, activating coagulation factors Factor V, Factor VIII, Factor XI and Factor XIII as well as cleaving fibrinogen and thus transforming it to the blood clot forming fibrin (also known as Factor Ia) (Uniprot: P02679). There are many known structures of thrombin, both in prothrombin and mature thrombin forms (for example see PDBe:2bvs).

Thrombin is a trypsin-like serine proteinase (Pfam:PF00089), and cleaves after arginine (and lysine) residues at the P1 position in substrates; Dabigatran is a substrate mimic (a peptidomimetic), with the phenylamidine mimicking the arginine sidechain.

Upon absorpotion, Dabigatran etexilate is readily metabolized to the active drug Dabigatran by ester hydrolysis at two distinct positions (therefore Dabigatran is dosed as a double prodrug). The charged groups of Dabigatran (the amidine and carboxylic acid) are poorly absorbed across membranes, and therefor the lipophilic ester and carbamate are added to mask these groups during oral dosing and absorption. Dabigatran is further metabolized to four different acyl glucuronides which are equally active as thrombin inhibitors. The absolute oral biovailability of Dabigatran (dosed as the prodrug) is 3-7%. The fraction of dabigatran bound to plasma proteins (ppb) is ~35% and volume of distribution (Vd) is 50-70L, clearance is primarily renal with a half-life (t1/2) of 12-14 hours.

Dabigatran etexilate is recommended for twice daily administration of 300mg (in two 150mg doses).

SMILES:

CCCCCCOC(=O)N=C(N)c1ccc(NCc2nc3cc(ccc3n2C)C(=O)

N(CCC(=O)OCC)c4ccccn4)cc1

InChI:

1S/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-

13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-

31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-

21,23H2,1-3H3,(H2,35,39,44)

Dabigatran etexilate is marketed under the trade name Pradaxa by

Boehringer Ingelheim.

Full prescribing information can be found here.

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

Mapping lists of IDs in ChEMBL

In order to facilitate the mapping of identifiers in ChEMBL, we have developed a new type of search in the ChEMBL Interface. Now, it is possible to enter a list of ChEMBL IDs and see a list of the corresponding entities. Here is an example: 1. Open the ChEMBL Interface , on the main search bar, click on 'Advanced Search': 2. Click on the 'Search by IDs' tab: 3. Select the source entity of the IDs and the destination entity that you want to map to: 4. Enter the identifiers, you can either paste them, or select a file to upload. When you paste IDs, by default it tries to detect the separator. You can also select from a list of separators to force a specific one: Alternatively, you can upload a file, the file can be compressed in GZIP and ZIP formats, this makes the transfer of the file to the ChEMBL servers faster. Examples of the files that can be uploaded to the search by IDs can be found here . 5. Click on the search button: 6. You will be redirected to a search resul

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

The ChEMBL-og

Search This Blog