New Drug Approvals 2013 - Pt. XVII - Macitentan (Opsumit ®)

ATC Code: C02KX (incomplete)

Wikipedia: Macitentan

On October 13th the FDA approved Macitentan (trade name Opsumit ®) for the treatment of pulmonary arterial hypertension (PAH). Macitentan is an endothelin receptor antagonist (with affinities to both Endothelin ET-A (ETA) and Endothelin ET-B (ETB) receptor subtypes, similar in mechanism of action to the previously licensed drug Bosentan, CHEMBLID957).

Target(s)
The Endothelin receptor ET-A (ETA, CHEMBLID252 ; Uniprot P25101) and Endothelin receptor ET-B (ETB, CHEMBLID1785 ; Uniprot P24530) receptors mediate a number of physiological effects via the natural peptide agonist Endothelin-1 (ET1 , CHEMBL437472 ; Uniprot P05305). In addition to normal roles in supporting homeostasis, these effects can include pathologies such as inflammation, vasoconstriction, fibrosis and hypertrophy.

Macitentan acts as an antagonist for both receptors with both a high affinity and long residence time in human pulmonary arterial smooth muscle cells. Hence it counteracts vasoconstriction and relieves hypertension. One of the metabolites of Macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro

Macitentan (CHEMBL2103873 ; Pubchem : 16004692 ) is a small molecule drug with a molecular weight of 588.3 Da, an AlogP of 3.67, 11 rotatable bonds, and 1 rule of 5 violation.

Canonical SMILES : CCCNS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1c3ccc(Br)cc3

InChi: InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)

Dosage

10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.

Metabolism and Elimination
Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. It is interesting to note the presence of bromine atoms in two of the aryl rings, typically a lighter halogen, typically fluorine is used to block oxidative P450-mediated metabolism at these exposed aromatic positions.

At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.

Pregnancy
Macitentan may cause fetal harm when administered to a pregnant woman. Macitentan is contraindicated in females who are pregnant.

Hepatotoxicity
Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Obtain liver enzyme tests prior to initiation of Macitentan and repeat during treatment as clinically indicated.

Hemoglobin Decrease
Decreases in hemoglobin concentration and hematocrit have occurred following administration
of other ERAs and were observed in clinical studies with Macitentan. These decreases occurred
early and stabilized thereafter Initiation of Macitentan is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.

Strong CYP3A4 Inducers / Inhibitors

Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure whereas concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir (CHEMBL163) are strong inhibitors of CYP3A4.

The license holder is Actelion Pharmaceuticals US the 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

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

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

The ChEMBL-og

Search This Blog