Skip to main content

New Drug Approvals - Pt. I - Milnacipran (Ixel/Savella)

An occasional series of posts with news and top level details on new FDA drug approvals. The series is a little retrospective at the moment, but it will not take much time to catch up for 2009.

First 'out of the gates' on 14th Jan this year is an 'old' compound, Milnacipran (Savella in the US) for the treatment of fibromyalgia syndrome. Milnacipran is an SNRI (Serotonin Norepinephrine Reuptake Inhibitor, and as such blocks the function of the norepinephrine transporter NET and the serotonin transporter SERT), like all compounds of this pharmacological class, the molecule is small (Molecular Weight of 246.4 g.mol-1 for Milnacipran itself, and 282.2 g.mol-1 for the HCl salt) is fully Rule-Of-Five compliant, has high aqueous solubility, and also has good oral absorption (85% bioavailable) and metabolism characteristics. (A plasma half-life of ca. 8 hours, a volume of distribution of 400L, low plasma protein binding at 13%. Excretion is renal (through the kidneys and urine) and excretion is primarily of the unchanged drug (55% unchanged). With a molecule like this, it should come as no surprise that it is delivered orally. Recommended dosage is 100mg (or ~354µmol, or ~177µmol of the pharmacologically active enantiomer, see below) per day, although dosing is phased from a low dose to 'full' dose over a week. Milnacipran is more potent at blocking norepinephrine uptake than serotonin uptake. The full prescribing information is here.

Milnacipran has a boxed warning (colloquially known as a 'black box').

Notable features of the chemical structure ((±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1- phenylcyclopropanecarboxamide hydrochloride) are the primary amine (the NH2) which is basic (it can be protonated and therefore positively charged), which will dominate its physicochemical properties. The remainder of the molecule is quite lipophillic. Of further note is the cyclopropane ring (the triangle part in the middle), which is completely rigid and will dominate the three-dimensional properties (shape) of the drug. The functional groups attached to the cyclopropane are attached with mixed stereochemistry, so the drug is 'racemic' - for this reason stereochemistry is not explicitly shown on the the 2-D structure below. However, the stereoisomers have different pharmacological activity, with the 'active' d-isomer having different properties (e.g. a longer half-life) to the 'inactive' l-isomer Finally, the approved drug is not Milnacipran itself, but the Hydrochloride salt (so in the tablet the amine is indeed protonated, as discussed above).

Milnacipran canonical SMILES: CCN(CC)C(=O)C1(CC1CN)C2=CC=CC=C2 Milnacipran InChI: InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3 Milnacipran InChIKey: GJJFMKBJSRMPLA-UHFFFAOYSA-N Milnacipran HCl CAS registry: 101152-94-7 Milnacipran CAS registry: 92623-85-3 Milnacipran (two enantiomers) Chemdraw: Milnacipran.cdx

I mentioned it was an old compound, well it is, just that old is relative. The SNRI/SSRI therapeutic classes are old ones, and several drugs of these related classes are now available generically. SSRIs and SNRIs are primarily 'antidepressant' drugs, and this compound itself has been used in certain countries for some time (Austria, since 1998, and also at least Chile and Israel), there has been much interest in expanding the clinical use of SSRIs/SNRIs beyond their original antidepressant actions. As one would expect, the commercial history of Milnacipran appears quite complicated, and the latest approval is for a 'new' therapeutic indication - fibromyalgia (chronic and widespread muscle pain). Fibromyalgia is a complicated disease with several competing theories for its causes, and is often associated/comorbid with depression.

The license holder for Milnacipran is Cypress Bioscience and the product website is www.savella.com

Finally, given the age of the compound, it would be interesting to know what the patent status of the compound is?

Comments

Popular posts from this blog

Improvements in SureChEMBL's chemistry search and adoption of RDKit

    Dear SureChEMBL users, If you frequently rely on our "chemistry search" feature, today brings great news! We’ve recently implemented a major update that makes your search experience faster than ever. What's New? Last week, we upgraded our structure search engine by aligning it with the core code base used in ChEMBL . This update allows SureChEMBL to leverage our FPSim2 Python package , returning results in approximately one second. The similarity search relies on 256-bit RDKit -calculated ECFP4 fingerprints, and a single instance requires approximately 1 GB of RAM to run. SureChEMBL’s FPSim2 file is not currently available for download, but we are considering generating it periodicaly and have created it once for you to try in Google Colab ! For substructure searches, we now also use an RDKit -based solution via SubstructLibrary , which returns results several times faster than our previous implementation. Additionally, structure search results are now sorted by

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen

Improved querying for SureChEMBL

    Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never

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