Software that phones home: Good or bad?

This is something that's been bugging me for a few days now - probably just triggered by reading all the recent disclosures of NSA/GCHQ surveillance, and trust in software systems in general. The basic issue I'm thinking about is when and where is it 'right' for software to 'phone home'?

This checking in with base idea is sometimes a good thing - for example if when I fire up a program, I get a little box that tells me a new version is available then that's a good thing. Or if my computer or phone is stolen, then calling in to let me know where in the world it is, is a good thing. It is probably also a good thing if you are a software vendor, and you want to ensure that your software hasn't been pirated, or run outside of the parameters for which it is properly licensed. For the latter case, it may even be a good idea to encrypt the message pinged back, to prevent l33t hax0rs suppressing license compliance mechanisms.

But the privacy issues of this sort of thing are very big, especially if, you as a user don't know it's being done, or if you don't know what is being sent back to base. I have only ever come across one software license (in this case a commercial vendor) that discusses this (in the context of the licensee not suppressing in any way this communication as a way of ensuring license compliance - not addressing at all what is sent back - if it's my source IP address and a timestamp fine, if it is a dump of all my queries, I'd be furious).

Of course, it's possible to control or spot this sort of activity, and I've just installed Radio Silence as a quick way of seeing if any of my desktop apps do anything behind the scenes I don't know about.

But, in general, are there any community expectations and standards for this sort of thing, especially for cases where the software will be used explicitly to generate trade secrets and perform confidential research?

USANS - February 2014

Just catching up on some recently published USAN statements.

USAN	Research Code	InChIKey (Parent)	Drug Class	Therapeutic class	Target
asvasiran-sodium	ALN-RSV01	n/a	RNAi	therapeutic	n/a
beclabuvir	BMS-791325	ZTTKEBYSXUCBSE-VSBZUFFNSA-N	synthetic small molecule	therapeutic	HCV NS5B polymerase
benzhydrocodone, benzhydrocodone-hydrochloride	KP-201	VPMRSLWWUXNYRY-PJCFOSJUSA-N	natural product derived small molecule	therapeutic	Opioid receptors
bradanicline, bradanicline-hydrochloride	TC-5619	OXKRFEWMSWPKKV-GHTZIAJQSA-N	synthetic small molecule	therapeutic	alpha-7 nicotinic acetylcholine receptor
briciclib, briciclib-sodium	ON-014185	LXENKEWVEVKKGV-BQYQJAHWSA-N	synthetic small molecule	therapeutic	n/a
ceritinib	NVP-LDK378-NX	VERWOWGGCGHDQE-UHFFFAOYSA-N	synthetic small molecule	therapeutic	ALK
dasabuvir	ABT-333	NBRBXGKOEOGLOI-UHFFFAOYSA-N	synthetic small molecule	therapeutic	HCV NS5B polymerase
defactinib, defactinib-hydrochloride	VS-6063	FWLMVFUGMHIOAA-UHFFFAOYSA-N	synthetic small molecule	therapeutic	FAK
dianhydrogalactitol	VAL-083, NSC-1323313	AAFJXZWCNVJTMK-UHFFFAOYSA-N	synthetic small molecule	therapeutic	DNA
dinutuximab	n/a	n/a	monoclonal antibody	therapeutic	GD2
diridavumab	CR-6261	n/a	monoclonal antibody	therapeutic	haemagglutinin
encenicline, encenicline-hydrochloride	EVP-6124	SSRDSYXGYPJKRR-ZDUSSCGKSA-N	synthetic small molecule	therapeutic	alpha-7 nicotinic acetylcholine receptor
esuberaprost, esuberaprost-sodium	APS-314d, BPS-314d	CTPOHARTNNSRSR-NOQAJONNSA-N	synthetic small molecule	therapeutic	IP1 receptor
filociclovir	MBX-400	KMUNHOKTIVSFRA-KXFIGUGUSA-N	synthetic small molecule	therapeutic	CMV DNA polymerase
fosdagrocorat	PF-04171327	n/a	synthetic small molecule	therapeutic	GR
gedatolisib	PF-05212384, PKI-587	DWZAEMINVBZMHQ-UHFFFAOYSA-N	synthetic small molecule	therapeutic	PI3K & mTOR
glasdegib	PF-04449913	SFNSLLSYNZWZQG-VQIMIIECSA-N	synthetic small molecule	therapeutic	smoothened
indoximod	D-1MT	n/a	natural product derived small molecule	therapeutic	IDO
latiglutenase	ALV-003	n/a	enzyme	therapeutic	n/a
lulizumab-pegol	BMS-931699	n/a	monoclonal antibody	therapeutic	CD28
ombitasvir	ABT-267	PIDFDZJZLOTZTM-KHVQSSSXSA-N	synthetic small molecule	therapeutic	HCV NS5a
omega-3-carboxylic-acids	n/a	n/a	natural product derived small molecule	therapeutic	n/a
peficitinib	ASP-015K	DREIJXJRTLTGJC-UHFFFAOYSA-N	synthetic small molecule	therapeutic	JAK
pegargiminase	n/a	n/a	enzyme	therapeutic	n/a
pembrolizumab	n/a	n/a	monoclonal antibody	therapeutic	Programmed cell death 1 (PDCD1)
polmacoxib	CG-100649	IJWPAFMIFNSIGD-UHFFFAOYSA-N	synthetic small molecule	therapeutic	COX-2
sarolaner	PF-6450567	FLEFKKUZMDEUIP-QFIPXVFZSA-N	synthetic small molecule	therapeutic	n/a
transcrocetinate-sodium	n/a	n/a	natural product derived small molecule	radiation sensitizer	n/a
uprosertib	GSK-2141795C	AXTAPYRUEKNRBA-JTQLQIEISA-N	synthetic small molecule	therapeutic	AKT1
venetoclax	ABT-199	LQBVNQSMGBZMKD-UHFFFAOYSA-N	synthetic small molecule	therapeutic	BCL-2

New Drug Approvals 2013 - Pt. XXIV - Sofosbuvir (Sovaldi ™)

ATC code (stem): J05AB

Wikipedia: Sofosbuvir
ChEMBL: CHEMBL1259059

On December 6, 2013, the FDA approved sofosbuvir for the treatment of patients with chronic hepatitis C infection. Sofosbuvir is intended for use as a component in combination treatments, depending on the type of hepatitis C either alongside Ribavirin alone, or in combination with both Ribavirin and peginterferon-alpha. Earlier in 2013, the FDA had already approved
Simeprevir for the treatment of this condition.

Hepatitis C is an infectious disease that affects primarily the liver and is caused by the hepatitis C virus (HCV), which belongs to the family of Flaviviridae and has a positive sense single stranded RNA genome of 9,600 nucleotides. Infection is mainly by blood-to-blood contact, through sharing or reuse of syringes or unsterilized medical equipment. Initially, the infection progresses without symptoms, and only becomes apparent in the chronic stages when liver damage leads to symptoms such as bleeding, jaundice, liver cancer and hepatic encephalopathy.

Sofosbuvir is a nucleotide analog inhibitor of the viral RNA polymerase (NS5b, Uniprot genome polyprotein: P26664, 2421-3011, PDB 3hkw). Viral RNA polymerases differ significantly from eukaryotic and bacterial polymerases both in sequence and three-dimensional structure. Thus, sofosbuvir inhibits only the amplification of the viral RNA genome and not endogenous transcription in the host organism by entering the polymerase as a substrate and terminating the transcript chain. The IC50 measured against NS5b ranged between 0.7 and 2.6 micro-molar, depending on the genotpye of the HCV isolate.

Structure of HCV NS5b, genotype 1a generated in pymol from PDB 3hkw.

 Sofosbuvir is a prodrug that is converted to the active form through a mono-phosphorylated intermediate. In contrast to other nucleotide analog inhibitors, the intermediate is formed in a step that cleaves off the groups attached to the phosphate group already present in sofosbuvir. This step is a lot faster than the enzymatic addition of a phosphate group that is required with other nucleotide analogs. The enzymes catalyzing this initial step include the lysosomal protective protein (Uniprot P10619), liver carboxylesterase 1 (Uniprot P23141) and Hint1 (Uniprot P49773). [1]

 Canonical SMILES: CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@@H](N2C=CC(=O)NC2=O)[C@](C)(F)[C@@H]1O)Oc3ccccc3 
Std-InChI: InChI=1S/C22H29FN3O9P/c1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1
Std InChI key: TTZHDVOVKQGIBA-IQWMDFIBSA-N

Sofosbuvir is an off-white crystalline substance that is slightly soluble in water. The molecular weight and logP are 529.45 Da and 0.92, respectively. Note the relatively low logP charateristic of nucleotide analog compounds.

The recommended daily dose of sofosbuvir is 400mg in a single tablet. Peak plasma concentration of the active metabolite are reached after 30-120 minutes post administration. The clearance is primarily through the kidney, with a half-life of 0.4 hours for sofosbuvir and 27 hours for its metabolite.  Sofosbuvir is a substrate of P-gp, and therefore inducers of P-gp, such as rifampicin and St John's wort are contraindicated for use with sofosbuvir.

Reported side effects of sofosbuvir include fatigue, headache, nausea, insomnia and anemia.

Sofosbuvir is marketed by Gilead under the name Sovaldi.

References:
[1] Murakami E, Tolstykh T, Bao H, Niu C, Steuer HMM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman P a: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285:34337–47.

HELM in ChEMBL

While the vast majority of molecules in ChEMBL are small molecules, we also have a growing collection of peptide-derived compounds, monoclonal antibodies and other biotherapeutic drugs in the database. Historically, these molecules have been represented by molfiles (for small-medium peptides) or protein sequences (for monoclonal antibodies) in the database.

However, for many biotherapeutics, these formats are not sufficient to represent the complexities of the molecules. Molfiles and other chemical structure formats are impractical for large molecules, and simple protein sequences cannot adequately capture the non-natural amino acids and other modifications that are commonplace in biotherapeutic drugs.

We are therefore working to adopt the HELM (Hierarchical Editing Language for Macromolecules) standard, developed by Pfizer and the Pistoia Alliance, within ChEMBL and plan to include HELM notation for all peptide-derived drugs and compounds in release 20 of the database.

See also the recent press-release for more information.

#ICanHazStructurez

I needed a pdf for a presentation I was giving this morning, I was in a hotel, which doesn't have an institutional subscription, so was stuck. On twitter, there is a hashtag #ICanHazPDF, which is quite successful, but to be clear I didn't use that route ;{o .

It got me thinking though, given the reach and immediacy of twitter, could I use it to get chemical structures - so #ICanHazStructurez was born. It worked, well in fact, and was very quick (see the image above - remember this was 6 am in the morning (in Germany at least).

So a big high five to @Lewis_Lab and @nickholway - FF and all that!

New Drug Approvals 2013 - Pt. XXIII Bazedoxifene (DUAVEE™)

   

wikipedia: bazedoxifene             

ATC code: G03XC02

On 3 October 2013, FDA approved a new drug, bazedoxifene in combination with estrogen (trade name DUAVEE™), for treatment of moderate-to-sever vasomotor symptoms (hot flashes) associated with menopause and the prevention of postmenopausal osteoporosis in women. Bazedoxifene reduces the risk of excessive growth of the uterus (endothermetrial hyperplasia) that can be caused by estrogen.

Bazedoxifene (IUPAC name: 1-{4-[2-(Azepan-1-yl)ethoxy]benzy}-2-(4-hydroxyphenyl}-3-methyl-1H-indole-5-ol) is an indole based small molecule of molecular weight of 470.6 g/mol, polar surface area of 57.9, seven rotatable bonds, four hydrogen bond acceptors and one hydrogen bond donor. The compound is lipophilic with alogP 7.22, ApKa 10.12 and logD of 5.17. The compound is also known as WAY-140424, Bazedoxifene Acetate, Bazedoxifene, SID144206564, or SID124893775.

Canonical Smiles: Cc1c(c2ccc(O)cc2)n(Cc3ccc(OCCN4CCCCCC4)cc3)c5ccc(O)cc15

Standard InchI: InChI=1S/C30H34N2O3/c1-22-28-20-26(34)12-15-29(28)32(30(22)24-8-10-25(33)11-9-24)21-23-6-13-27(14-7-23)35-19-18-31-16-4-2-3-5-17-31/h6-15,20,33-34H,2-5,16-19,21H2,1H3

Bazedoxifene is a selective estrogen receptor  modulator (SERM) with a unique tissue and selectivity profile. Estrogen receptor (PDBe: 4iwf), is a transcription factor, which upon activation by a ligand, binds to DNA and regulates gene expression by mediating post-translational modification of histones and the associated transcriptional proteins.

                                                              

Bazedoxifene is also known to prevent bone loss and osteoporotic fractures in postmenopausal women.  The drug, comes in the form of a tablet containing 0.45 mg estrogens and 20 mg bazedoxifene 20 mg. It is taken orally, once a day. Amongst other precautions, women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists. A detailed account of the prescribing information can be found here.

The license holders are Wyeth Pharmaceuticals, Inc. (a subsidiary of Pfizer Inc.,) based in Philadelphia, Pa.

New Drug Approvals 2013 - Pt. XXII - Luliconazole (Luzu ™)

ATC Code: D01AC (incomplete)

Wikipedia: Not Available

ChEMBL: CHEMBL2105689

On November 14th the FDA approved Luliconazole (trade name Luzu ^TM) for the treatment of skin fungal infections including ringworm. Luliconazole inhibits fungal synthesis of ergosterol, required for fungal cell membranes, by inhibiting the enzyme cytochrome P450 14-alpha-demethylase (P45014DM). 

Target(s)
Like all azole antifungals, Luliconazole binds and inhibits fungal 14-alpha-demethylase (e.g. CHEMBL1681624, Uniprot Q96W81).  P45014DM is a cytochrome P450 that catalyses the oxidative removal of the 14α-methyl group from eburicol to ergosterol. Azoles bind to the haem in P45014DM via the unprotonated N atom and occupy the active site as non-competitive inhibitors.

Luliconazole (CHEMBL2105689; Pubchem : 144206495 ) is a small molecule drug with a molecular weight of 354.3 Da, an AlogP of 4.03, 2 rotatable bonds, and no of 5 violations.

Canonical SMILES : Clc1ccc([C@@H]2CS\C(=C(\C#N)/n3ccnc3)\S2)c(Cl)c1

InChi: InChI=1S/C14H9Cl2N3S2/c15-9-1-2-10(11(16)5-9)13-7-20-14(21-13)12(6-17)19-4-3-18-8-19/h1-5,8,13H,7H2/b14-12+/t13-/m0/s1

Dosage

Each gram of Luzu Cream, 1% contains 10 mg of luliconazole in a white cream base.

For treatment of Interdigital Tinea Pedis: Luzu Cream, 1% should be applied to the affected and immediate surrounding area(s) once a day for two weeks.

For treatment of Tinea Cruris and Tinea Corporis: Luzu Cream, 1% should be applied to the affected skin and immediate surrounding area(s) once a day for one week.

Drug Interactions 

The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe Tinea Cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4. 

Pregnancy
Luliconazole is classified as pregnancy category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

The license holder is Valeant Pharmaceuticals, the highlights of the prescribing information can be found here.

New Drug Approvals 2013 - Pt. XXI - Eslicarbazepine Acetate (AptiomTM)

Wikipedia: Eslicarbazepine Acetate

On November 8th 2013, FDA approved Eslicarbazepine Acetate (tradename: Aptiom; research codes: Sep-0002093, BIA 2-093; ChEMBL: CHEMBL87992), a prodrug indicated as adjunctive treatment of partial-onset seizures associated with epilepsy.

Epilepsy is neurological disorder characterised by abnormal neuronal activity in the brain. Partial-onset seizures, as opposed to generalised seizures, affect initially only one part of the brain and, depending on the part of the brain that is affected, these seizures will present different symptoms.

Eslicarbazepine (ChEMBL: CHEMBL315985), the bioactive ingredient of the prodrug Eslicarbazepine Acetate, exerts its anticonvulsant activity by blocking the voltage-gated sodium channel (VGSC). VGSC has 3 distinctive states: the resting state, during which the VGSC is closed but responsive to a depolarisation impulse, the open state, during which the channel is open allowing the sodium ion to enter the cell, and the inactivated state, in which the channel is closed again but irresponsive to voltage changes. Eslicarbazepine binds and stabilises the inactive form of the VGSC, preventing its reversion to the resting form and limiting sustained repetitive neuronal firing.

VGSC (ChEMBL: CHEMBL2331043) is a single alpha-subunit with four repeat domains each containing six transmembrane segments. A 3D structure of the VGSC in an open conformation (PDBe: 4f4l) is shown below.

Eslicarbazepine Acetate is a synthetic small molecule with a molecular weight of 296.3 g.mol^-1, an ALogP of 2.4, 3 hydrogen bond acceptors, 1 hydrogen bond donor, and therefore fully compliant with Lipinski's rule of five.
IUPAC: [(5S)-11-carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl] acetate
Canonical Smiles: CC(=O)O[C@H]1Cc2ccccc2N(C(=O)N)c3ccccc13
InCHI: InChI=1S/C17H16N2O3/c1-11(20)22-16-10-12-6-2-4-8-14(12)19(17(18)21)15-9-5-3-7-13(15)16/h2-9,16H,10H2,1H3,(H2,18,21)/t16-/m0/s1

The recommended starting dosage of Eslicarbazepine Acetate is 400 mg once daily. After one week, the dosage should be increased to 800 mg once daily (recommended maintenance dosage). The maximum recommended maintenance dosage is 1200 mg once daily (after a minimum of one week at 800 mg once daily).

After oral administration, Eslicarbazepine Acetate is mostly undetectable, since it is extensively and rapidly metabolised by hydrolytic first-pass metabolism to its major active metabolite, Eslicarbazepine, corresponding to 91% of systemic exposure. Eslicarbazepine is highly bioavailable with an apparent volume of distribution of 61L for body weight of 70Kg, a relatively low plasma protein binding (< 40%) and an apparent half-life in plasma of 13-20 hours. Other minor active metabolites of Eslicarbazepine Acetate include (R)-Liscarbazepine and Oxcarbazepine, corresponding to 5% and 1% of systemic exposure, respectively. Eslicarbazepine Acetate metabolites are eliminated mainly by renal excretion, in the unchanged and glucuronide conjugated forms, with Eslicarbazepine and its glucuronide accounting for more than 90% of total metabolites excreted in urine.

The licensed holder of Eslicarbazepine Acetate is Sunovion Pharmaceuticals Inc. and the full prescribing information can be found here.

ADME SARfari: A tool for predicting and comparing cross-species ADME targets

ADME studies are focused on understanding the disposition of a compound within an organism and the results of such studies play a critical role in the drug development process. ADME studies (more commonly referred to as pharmacokinetic or PK studies) are focused on 4 main areas: Absorption, Distribution, Metabolism and Excretion. More information on the PK measurement types can be found here.

Comparisons of PK data across species is a potential problem drug researchers need to deal with, as model organism studies are the primary source of such data. For example, in an animal model study, which may be carried out on a compound as it passes through the drug development pipeline, is it meaningful to compare clearance or bioavailability data from a mouse or rat to human? Clearly there are many differences (physical, metabolic, genetic,..), which make answering these types of questions difficult. Building tools which guide researchers to potential answers or provide a better understanding of the inter-species differences are of great value - leading us nicely to the focus of this blog post.

It turns out the ChEMBL database has a wealth of PK measurements data, which allows users to start asking ADME focused questions. You can access all of this data via the ChEMBL Interface or from one of our downloads, but in order to answer some of the more complex questions a significant amount of data processing first needs to take place. So to help the ChEMBL community get started analysing this data, we, in collaboration with our colleagues at GSK, set about building a new ADME focused system. The new system is called ADME SARfari and it aims to centralise all ADME data currently stored in ChEMBL and other related databases, as well as providing new tools to help interrogate the data.

In order to build the system we have pulled data from a number of sources, which include:

• ChEMBL - Bioactivity data, PK data and molecules.
• PharmaADME - An online resource providing a list ADME related human genes. We used this to build our primary list of ADME Targets, but have also added a couple of extra ones.
• The Human Protein Atlas -  Protein expression data for human ADME Targets.
• ENSEMBL - Orthologue (using the Compara Service) and SNP data for ADME Targets.
• The Göttingen minipig and beagle dog genome predicted ADME Targets. GSK have sequenced the  genomes of these two pharmaceutically significant species. More details on the genomes can be found here.

When you visit the site you will find it is divided into the following 7 sections:

• Home - Allows user to initiate a compound or protein focused search.
• Orthologues - A table of ADME orthologues. The first column of the table corresponds to the human ADME targets and additional columns correspond to targets found in model organisms.
• Tissues - Protein expression data for human ADME targets.
• Bioactivities - Bioactivity data and PK measurements for all ADME related targets in the system, which are also found in the ChEMBL database.
• Molecules - Distinct set of ChEMBL molecules linked to ADME related targets via the bioactivity data.
• Pharmacokinetic - A cross species comparison of PK data for compounds found in the  ChEMBL database  (see red heatmap image at top).
• About - More details on how to use the system

By clicking on the links above, you can view and download all of the data associated within each of the sections. One exception is the Pharmacokinetics section, as there is too much data to display in the heatmap by default, so you must first initiate a search (we will come back to this later). Now that you have a better idea of what is in the system, what are the types of questions you can ask? Looking at the homepage you will see there are 2 ways to initiate a search of the system: Compound-initiated, using the chemical sketcher box and protein-initiated, using the BLAST or keyword search.

Protein Search  (Using BLAST)

To run a BLAST search paste a sequence in the text box to the right on the homepage:

BLAST search results will be displayed on the Orthologues page and only rows which contain hits to your search query will be returned:

Clicking on the Tissues tab displays the protein expression levels of the human targets returned by the BLAST search:

Clicking on the Bioactivities tab returns all of the ChEMBL bioactivity data for targets returned by BLAST search:

Clicking on the Molecules tab returns the distinct set of compounds currently displayed in the Bioactivities section:

Clicking on the Pharmacokinetics tab will provide a cross-species overview of the PK data in ChEMBL for the compounds currently displayed in the Molecules section (Note that not all compounds will have PK measurements):

The following points help explain what the heatmap above is displaying:

• Each narrow row corresponds to a compound.
• Each column corresponds to a PK measurement in a specific organism. 
• The PK measurements summarised in this view are Clearance (Cl), Cmax, Bioavailability (f), T1/2, Tmax and Volume of Distribution (Vd). 
• The colour of each cell corresponds to a low, medium and high binned PK measurement, making it easier to compare values across species.
• The columns can be sorted by clicking on the header (see the second column, which corresponds to the Human Clearance data).

Compound Search

It is also possible to search the system using a compound structure. Simply draw or paste a structure into the compound sketcher on the left of the homepage:

 

You can then choose to run a substructure and similarity search. When you run the search you will first be taken Molecules section and you can then explore the other sections, which are all connected based on this initial set of compounds.

Predictive Model Search

The system also allows a user to predict which ADME protein target a molecule will interact with. The binding data (displayed in the Bioactivities section) has been used to build a multi-category naive Bayesian  classifier. We will follow up with a more detailed post describing the model building process, but essentially the model is able to predict if a user-submitted molecule will interact with 133 of the ADME targets included in the system. The About page provides some additional data on the targets included in the model. 

To run a search against the predictive model, draw or paste a structure into the compound sketcher on the left of the homepage and hit the "Model Prediction" button. You will be taken to the Orthologues section, but only the rows which include a target predicted to interact with submitted molecule (coloured green) will be on display:

We hope you find the ADME SARfari system useful and if you have any questions please let us know.

The ChEMBL Team

New Drug Approvals 2013 - Pt. XX - Simeprevir (OlysioTM)

ATC Code: J05AE14
Wikipedia: Simeprevir

On November 22^th 2013, the FDA approved simeprevir (Tradename: Olysio; Research Code(s): TMC-435; TMC435350), a Hepatitis C virus NS3/NS4A protease (HCV NS3/NS4A) inhibitor, for the treatment of chronic hepatitis C virus genotype 1 infection, in combination with peginterferon alfa and ribavirin.

Chronic hepatitis C is a prolonged infection that affects the liver and is caused by a small single-stranded RNA virus, which is transmitted by blood-to-blood contact. Chronic hepatitis C is normally asymptomatic, but may lead to liver fibrosis, and thus liver failure.

Simeprevir is an inhibitor of the hepatitis C virus (HCV) serine protease NS3/NS4A (ChEMBLID:CHEMBL2095231; Uniprot ID:A3EZI9, D2K2A8; Pfam:PF02907), a viral protein complex required for the proteolytic cleavage of the HCV encoded polyprotein (UniProt:P27958) into mature forms of the NS4B, NS5A and NS5B proteins. These proteins are involved in the formation of the virus replication complex, and therefore are vital to its proliferation. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively. However, in patients infected with the genotype 1a hepatitis C virus with an NS3 Q80K polymorphism, the effectiveness of simeprevir is slightly reduced, thus, screening for this polymorphism prior to the beginning of therapy is recommended, and alternative therapies should be considered.

There are several protein structures known for HCV NS3 in complex with inhibitors, a typical entry is PDBe:3rc4, as expected from early genome annotation, the NS3 protease has a fold distantly related to the chymotrypsin-like family of serine proteases, and contains the classic Asp-His-Ser catalytic triad.

The -vir USAN/INN stem covers antiviral agents, and the substem -previr indicates it is a serine protease inhibitor. Simeprevir is the third approved agent to target HCV NS3/NS4A, following the approval of Merck's Boceprevir (q.v.) and Vertex's Telaprevir in 2011. Contrary to its predecessors, simeprevir is a natural derived compound, which requires a substantial lower dose (~16x less) for an effective response. It is also once-daily dosed, offering thus a promising alternative therapy for potential non-complying patients. Other compounds in this class in late stage clinical development/registration or earlier stages of development include Genentech's Danoprevir (RG-7227, ITMN-191), Bristol Myers Squibb's Asunaprevir (BMS-650032), Vaniprevir (MK-7009), Schering's Narlaprevir (SCH-900518), Achillion's Sovaprevir (ACH-0141625), Gilead's Vedroprevir (GS-9451), Ciluprevir (BILN-2061), ABT-450, BI-201335, IDX-320, MK-5172, BIT-225, VX-500, ACH-1625 and GS-9256.

Simeprevir (IUPAC Name: (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide; Canonical smiles: COc1ccc2c(O[C@@H]3C[C@@H]4[C@@H](C3)C(=O)N(C)CCCC\C=C/[C@@H]5C[C@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)cc(nc2c1C)c7nc(cs7)C(C)C; ChEMBL: CHEMBL501849; PubChem: 24873435; ChemSpider: 23331536; Standard InChI Key: JTZZSQYMACOLNN-VDWJNHBNSA-N) is a a natural product derived compound, with a molecular weight of 749.9 Da, 9 hydrogen bond acceptors, 2 hydrogen bond donors, and has an ALogP of 4.8. The compound is therefore not fully compliant with the rule of five.

Simeprevir is available as an oral capsule and the recommended daily dose is a single capsule of 150 mg. In HCV-infected subjects, the steady-state is reached after 7 days of once daily dosing and the mean steady-state AUC₂₄ is 57469 ng.h/mL (standard deviation: 63571). Simeprevir should be administered with food, since food enhances its bioavailability by up to 69%. In vitro studies indicated that simeprevir is extensively bound to plasma proteins (greater than 99.9%).

The primary enzymatic system involved in the biotransformation of simeprevir in the liver is CYP3A. Therefore, co-administration of simeprevir with inhibitors or inducers of CYP3A may significantly alter the plasma concentration of simeprevir. In vitro studies indicated that simeprevir is a substrate of P-gp, and is transported into the liver by OATP1B1/3. Following a single oral administration of 200mg, the terminal elimination half-life of simeprevir is 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects. Elimination of simeprevir occurs via biliary excretion, and its metabolites are primarily excreted in feces.

As simeprevir is given as a component of a combination antiviral treatment regime with ribavirin and peginterferon alfa, there is a warning for embryofetal toxicity.

The license holder for Olysio^TM is Janssen Pharmaceuticals, and the full prescribing information can be found here.