ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Thursday, 31 March 2011

World Malaria Day 2011

World Malaria Day for 2011 is on April 25th again this year - see the worldmalariaday website for more details. Also look at the ChEMBL-NTD website for some relevant data from the ChEMBL resources.

Tuesday, 29 March 2011

Registration now open for the ChEMBL User Group (ChUG) meeting

Registration is now open on the LinkedIn ChEMBL User Group page for our first meeting. If you are not on LinkedIn and would still like to come, please mail me.

To parents of young children the world over (in 175 territories in fact) the image above will be too familiar.

Monday, 28 March 2011

New Drug Approvals 2011 - Pt. IX Ipilimumab (YervoyTM)

ATC code:L01XC11

On 25th March 2011, the FDA approved Ipilimumab (trade name YervoyTM, ATC code:L01XC11), a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for the treatment of unresectable or metastatic melanoma. (MelanomaCRUK melanoma; OMIM: 155600; ICD: C43).

Malignant melanoma is diagnosed in an estimated 160,000 new patients each year and, despite being less common than other skin neoplasms, it is responsible for 75% of skin cancer-related deaths. Current available treatment options for melanoma are limited to surgery, chemotherapy, radiotherapy and immunotherapy, although there are a number of targetted agents in the clinical development at the moment. Ipilimumab effect in melanoma is indirect and probably due to enabling a T-cell mediated immune response

In a randomised clinical study that assessed the response of unresectable or metastatic melanoma patients to Ipilimumab, alone and in combination with investigational peptide vaccine adjuvant, gp100, the combination showed increased survival time (median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone) as well as a near doubling of the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%) as compared to the peptide alone.

Ipilimumab's molecular target is CTLA-4 (Uniprot: P16410canSAR ; PFAM: P16410), a negative regulator of T-cell activation. Ipilimumab augments T-cell activation and proliferation by binding to CTLA-4 and preventing its interaction with its ligands (CD80 and CD86). CTLA-4 is a membrane-bound, 223 amino acid long, T-cell protein. It contains an immunoglobulin V-type domain (PFAM:PF07686). The structure of CTLA-4 is determined (see e.g. PDBe:3osk)Ipilimumab has been issued with a Black Box warning as it can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation, particularly enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.

Ipilimumab is administered intravenously, and the recommended dose is 3 mg/kg administered over 90 minutes every 3 weeks for a total of four doses. The terminal half-life (t1/2) is 14.7 days (30.1%); systemic clearance (CL) is 15.3 mL/h (38.5%); and volume of distribution at steady-state (Vss) is 7.21 L (10.5%). 

The full prescribing information can be found hereYervoy™ is a product of Bristol-Myers Squibb

Saturday, 26 March 2011

A UK Academic Network for Chemical and Structural Biology in Drug Discovery

This Network will establish an Academia-Users Network in Chemical Biology to initiate, establish and nurture collaborative projects for the advancement of the drug discovery process. It aims to expand the capability of UK drug discovery, with new drug targets, new tools to validate targets and new multidisciplinary partnerships to explore the platforms, tools and targets of the future.

A poster for this new network is above, but a website is being set-up for this, and as soon as it is ready to go, we'll provide links on the ChEMBL-og.

The network is funded by the EPSRCBBSRC and MRC, funded through their joint “Collaborative Networks in Chemical Biology” initiative.

Thursday, 24 March 2011

Conference: 4ECCLS, Budapest, August 31-September 3 20117 2011

There's a great looking conference in Budapest this August, the 4th European Conference on Chemistry for Life Sciences (4ECCLS) - a link to the conference website is

Tuesday, 22 March 2011

A Taxonomy for Drugs: 3 - Antibody subtypes

There is an excellent description of specific subtypes of monoclonal antibodies on Wikipedia, these can be easily incorporated into the Drug_Class section of our drug taxonomy. Specifically as Drug_Type_Subsubclass. An interesting property of this classification is that it should be possible to write an algorithm that classifies arbitrary sequences against this taxonomy.

  • mab - whole monoclonal antibody.
  • Fab - fragment, antigen-binding (one arm).
  • F(ab')2 - fragment, antigen-binding, including hinge region (both arms).
  • Fab' - fragment, antigen-binding, including hinge region (one arm).
  • scFv - single-chain variable fragment.
  • di-scFv - dimeric single-chain variable fragment.
  • sdAb - single-domain antibody.
  • 3funct - trifunctional antibody.
  • BiTE - bi-specific T-cell engager.
  • Other - an antibody like drug that does not fit one of the above classes.

Monday, 21 March 2011

Developer position in ChEMBL available

We now have an immediately available position within the ChEMBL group for an exciting project looking at data integration of ADMET data alongside structural and comparative genomics data. This role requires good general bioinformatics knowledge, programming in perl (or equivalent), knowledge of SQL, and database querying and data integration. Previous experience with ADMET data would be beneficial.

More details are available on request.

Thursday, 17 March 2011

ChEMBL Web Services are now in BioCatalogue

BioCatalogue is a registry of Web Services in the biosciences. All the ChEMBL web services (including the REST and SOAP PSICQUIC) services are now listed in BioCatalogue.

New Drug Approvals 2011 - Pt. VIII Gadobutrol (GadavistTM)

ATC code : V08CA09

On March 14th 2011, the FDA approved Gadobutrol (USAN: Gadobutrol USANdate: 2010 tradename: Gadavist NDA 201277), a gadolinium-based contrast agent, for intravenous (i.v.) use in diagnostic MRI to detect and visualize areas with disrupted blood brain barrier and/or abnormal blood supply of the central nervous system. In MRI, when an electromagnetic field is applied, the hydrogen nuclei present in the body, flip their spin and align with the direction of the field. Once the field is turned off, the hydrogen nuclei decay to the original spin-down state and release a photon, corresponding to the energy difference between the two states. Since, hydrogen nuclei in different tissues return to their equilibrium state at different rates, a distinctive image can be obtained. Gadobutrol enhances the contrast in MIR images, by decreasing the spin-lattice relaxation time (T1) and the spin-spin relaxation time (T2).

The gado- USAN/INN stem covers gadolinium derivatives used for diagonistic/imaging use; other approved drugs from the V08CA ATC class include gadoteridol, gadoversetamide, gadodiamide, gadobenic acid, gadopentetic acid, gadoxetic acid and gadofosveset acid.

Gadobutrol (IUPAC: 2-[4,10-bis(2-oxido-2-oxoethyl)-7-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetrazacyclododec-1-yl]acetate; gadolinium(3+) PubChem: CID 15814656) is a gadolinium(III)(Gd3+) chelate with two chiral centers. It has a molecular weight of 604.7 Da, and contains three hydrogen bond donors and thirteen hydrogen bond acceptors.

In comparison with the other gadolinium chelates, gadobutrol has a macrocyclic framework and is overall neutral in charge.

Gadobutrol is dosed intravenously, with a recommended dose of 0.1 mL/kg body weight (0.1 mmol/kg). It is more concentrated than other gadolinium-based contrast agents and should be administered at half of the volume. Gadoburtol is cleared from the plasma, after an intravenous injection (iv) with a mean terminal half-life (t1/2)of 1.81 hr. It is excreted in an unchanged form via the kidneys.

Gadavist has a black box warning and should not be used in patients with impaired elimination of drugs. It may increase the risk of nephrogenic systemic fibrosis (NSF).

The license holder for Gadavist is Bayer HealthCare Pharmaceuticals, the product website is here, and the full prescribing information can be found here (Gadobutrol was approved in the EU in 2000 under the tradename Gadovist, the European SPC can be found here).

Wednesday, 16 March 2011

Webinar - ChEMBL Web Services and Schema Walkthrough

We plan to run some webinars detailing recent progress and changes with some of our services.

The first will be a webinar on the ChEMBL REST web services and programmatic access at 3 pm BST on 31st March 2011. Please mail to register for this.

The second will be a webinar on the current ChEMBL schema at 3pm BST on 30th March 2011. Please mail to register for this.

Please note that at this time of year, not all countries are synchronised on the transition to Daylight Savings time (if indeed they do change). Please check mapping of your local time to BST. Please, please try and resist the temptation to edit the subject lines of the mail links above.

Friday, 11 March 2011

Visitor Talk - Jens Loesel - MedChem Attractiveness and Redundancy - Looking for value in Compounds and Chemical Space

We have a visitor to the EBI on 6th April 2011 - Jens Loesel from Pfizer, Sandwich. Jens will give a talk at 1pm on some large-scale cheminformatics analysis of the Pfizer screening file that he has done. If any off campus people want to come to the talk, they are very welcome; but I will need a name and affiliation to get them past security - mail me. An abstract for the talk is below....

MedChem Attractiveness and Redundancy - 
Looking for value in Compounds and Chemical Space
Jen Loesel, Pfizer

A more diverse screening file is a better screening file. A bigger screening file is a better screening file. Are these statements really true? We will critically scrutinize both these questions in the talk.
In part 1 we will investigate the quality of chemical structures. A good screening file needs to balance quality versus diversity.

We generated an algorithm that is purely based on structure to achieve this. The algorithm is able to compete with medicinal chemists in ranking the attractiveness of compounds as defined by the consensus opinion of multiple chemists. We called the score MedChem Attractiveness (MCA ). The score is an important step towards quantifying the quality of chemical structures. The score complements existing algorithms for novelty and diversity as well as filters like the Ro5.

In part 2 of the talk we look at the size and economy of the screening file. The value of the whole screening file isn’t simply the sum of all its individual compounds. There is a limit at which a screening file becomes too big and costly for the aim it tries to solve – finding new leads for novel MedChem projects in an efficient manner?

Primary screens at Pfizer often yield large numbers of very similar hit compounds. These large clusters of active compounds represent limited value for Hit Identification beyond the first few active members. To streamline our screening operation we analysed the probability of finding actives in recent HTS screens based on fingerprint similarity. We combined the results from the HTS analysis with Belief Theory. This allowed us to define the ideal density of neigbours in chemical space for lead identification. Based on that density we defined a new property of the chemical space we call Redundancy. Redundancy represents the fraction of compounds populating chemical space beyond the ideal density for efficient Hit Identification screening.

This work was no academic exercise. The model resulted in the permanent deletion of >1 million compounds from the screening file. The result is a higher quality and more efficient Pfizer screening file for the future. Both algorithms are very generic and can be applied or adapted to a variety of other uses.

Thursday, 10 March 2011

New Drug Approvals 2011 - Pt. VII Belimumab (BenlystaTM)

ATC code : L04AA26

On March 9th, 2011, the FDA approved Belimumab (trade name: Benlysta, ATC code L04AA26), an immunosuppressant human monoclonal antibody, for treatment of patients with systemic lupus erythematosus (SLE, OMIM:152700, ICD-10:M32.), a systemic autoimmune disease. The prevalence of SLE varies among differing ethnic groups, and countries, e.g. 40 per 100,000 in Northern Europe, 53 in 100,000 in the US, and 159 in 100,000 among people of Afro-Caribbean descent; this translates to about 159,000 cases in the US, among 1.5 million cases of different forms of lupus in general. In SLE, periods of illness alternate with remissions, and symptoms are diverse, comprising fever, malaise, joint pains, myalgias, and fatigue, but also dermatological symptoms (e.g. malar rash), anemia, cardiac, pulmonary and renal impairments as well as neurological and neuropsychiatric syndromes such as headache and depression, rendering diagnosis challenging. SLE is currently incurable, and its symptomes are traditionally treated with powerful agents such as cyclophosphamide, corticosteroids and immunosuppressants.

Belimumab acts by binding to the soluble form of B-lymphocyte stimulator (BLyS, a.k.a. BAFF, TNFSF13B, CD257, Uniprot:Q9Y275 Pfam:PF00229), a member of the TNF superfamily of proteins. BLyS promotes the survival and development of B-lymphocytes into mature plasma B cells; these key immune system cells produce antibodies, mediating the humoral immune response. BLyS was discovered for its immune stimulant properties in 1999 by Human Genome Sciences (HGS), who jointly with GSK then developed Belimumab as an effective BLyS inhibitor, and ultimately the first new lupus drug since 1955.

As the name Belimumab implies, it is a human (-u-) immunomodulatory (-lim-) antibody.

The structure of the soluble form of BLyS is known, a typical pdb entry is 1kxg.

After reconstitution of lyophilized powder, Benlysta is diluted to the recommended dosage of 10 mg/kg and injected intravenous at 2-week intervals for the first 3 doses, and at 4-week intervals thereafter. The distribution half-life (t1/2) of Belimumab is 1.75 days, the terminal half-life (t1/2) is 19.4 days, with a steady state Volume of distribution (VSS) of 5.29 L, and a Clearance (Cl) of 215

The full prescribing information can be found here, and the product website is here.

Benlysta is manufactured by HGS and marketed by HGS and GSK.

Sunday, 6 March 2011

A Taxonomy for Drugs: 2 - Stereochemistry

The next area for consideration in our descriptive taxonomy for drugs is stereochemistry. There are many differing types of stereoisomers encountered in general chemistry, and the area is complex, but the majority of these are not relevant for drug discovery; for example atropisomers, although an important effect is not important for among drug substances. The most significant category of stereochemistry for drug like molecules involves chiral centers at sp3 hybridised carbon atoms connected to four chemically distinct atoms (often giving rise to enantiomerism). Another relevant case of stereoisomerism for drugs are diastereoisomers, these are stereoisomers that are not enantiomers, and include cis-/trans- (E-/Z-) configuration of alkenes.

So for Drug_Stereochemistry_Class, a drug can be:
  • Chiral - containing a single defined stereoisomer of the drug substance, and which lacks an internal plane of symmetry.
  • Racemic - containing a mixture of stereoisomers of the drug substance.
  • Achiral - composed of a drug substance that does not display chirality.
  • Other - displaying a physiologically relevant stereochemical property not covered by the classes above.
The vast majority of biological monomers (e.g. amino acids, nucleotides, sugars)  are chiral, and polymers of these are also chiral (so biological drugs and drug targets within the body). So biological drugs are 'chiral', but since it is so ubiquitous for molecules of this class, the convention is to ignore the issue of chirality for biologicals. For small molecule drugs, the importance is more significant, both scientifically and commercially, and several drugs which were initially synthesized and marketed as racemic mixtures, have subsequently been developed in a chirally pure form. An example of this is Omeprazole, which was subsequently replaced by the 'active' S-enantiomer Esomeprazole. By convention, USANs and INNs for chirally distinct forms of a molecule have either ar- as a prefix for R-configuration and es- as a prefix for S-configuration forms. There is no correlation between the +/- labelling and R/S labelling of chirally active molecules. Previously, the USANs/INNs of chirally pure drugs were often denoted with levo- and dextro- prefices.

It is important to note that since drugs tend to interact with chiral receptors, enantiomers will have different binding affinities against a target (or set of targets), metabolic routes, side-effects, half-lives, etc., and so in general there is usually more interest in developing a chirally pure or achiral drug. Chiral centers often add significantly to the synthetic complexity and cost of manufacture of a drug, and so again there are pressures to develop achiral drugs where possible. So as a general rule, achiral drugs are 'preferred' over chiral drugs which in turn are preferred over racemic drugs. There is a fuller discussion of isomerism and drug development here.

Although most chirality in drugs occurs at sp3 carbon atoms, an important and often neglected case is for sulfoxides, where the geometry around the sulphur atom is tetrahedral, and optically active isomers are possible.

For example:

Sildenafil is an achiral drug.
Levodopa is a chiral drug.
Armodafanil is a chiral drug (containing a chiral sulfoxide).
Citalopram is a racemic drug.
Abciximab is a chiral drug.

Friday, 4 March 2011

A Taxonomy for Drugs: 1 - Drug Class

It is intuitive to describe what a drug is in natural language - a small molecule, etc, but one problem is that these descriptive terms are context dependent, loosely defined and are used very variably across the literature; and so when someone asks 'How many small molecule drugs there are?' - first of all it depends on what is a 'drug', and secondly what is a 'small molecule'. As far as I can tell there is not a descriptive taxonomy for drugs (I use the term taxonomy here as a bridge term between a controlled vocabulary/dictionary and an ontology). For our own purposes within ChEMBL we need such a taxonomy, but post our initial thoughts here for comment, and no doubt (and hopefully), significant correction and improvement (use the comment section of the blog, then everyone can see any discussions).

Drugs are regulated products that are 'intended use in the diagnosis, cure, mitigation, treatment or prevention of disease' - let's not visit what a disease is, but move swiftly on to trying to sub divide this into obvious and useful categories/classes when thinking about molecular drug structures.

So for a Drug_Class, categorisation into the following seems intuitive and useful. Most of the action in drug discovery will be connected to the "Therapeutic" class.
  • Therapeutic - A substance with a curative action on a disease.
  • Supplement - A substance, used to address a deficiency of that substance (or of that substances normal function).
  • Imaging Agent - A substance used to image a molecule or structure within the body.
  • Diagnostic Agent - A substance used in the diagnosis of a disease, not involving imaging.
  • Other - A substance not covered by the categories above.
Drugs are then typically divided into Drug_Types - small molecules and biologicals.
  • Small Molecule - A substance with a molecular weight less than 1500 Da that is otherwise not a Biological.
  • Biological - A substance primarily composed from monomers of naturally occuring substances (e.g. amino-acids, sugars, nucleotides, etc.).
  • Other - A substance not covered by the categories above.
I hate these sort of self referential/recursive definitions, but please mail improvements! Within each of these two main classes there are some relevant, pragmatic and useful subdivisions - Drug_Type_Subclass.

For Small Molecules:
  • Inorganic - A non-organic substance.
  • Natural Product-derived - A substance that is derived from a naturally occurring primary or secondary metabolite.
  • Synthetic - An organic substance that is not derived from a naturally occurring priamry or secondary metabolite.
  • Other - A substance that is a Small Molecule which is not covered by the categories above.
For Biologicals:
  • Monoclonal antibody (mAb) - A substance similar in sequence to an antibody sequence.
  • Vaccine - A substance that acts through eliciting an acquired immune response in the patient.
  • Enzyme - A substance acting as a catalyst for a chemical reaction.
  • Virus - A substance with the biological characteristics of a competant virus.
  • Cell - A substance with the biological characteristics of a competant cell.
  • Peptide - A substance which is a polymer built primarily from amino acids, containing between two and twenty amino acids.
  • Protein - A substance which is a polymer built primarily from amino acids, containing in excess of twenty amino acids, and that is not a monoclonal antibody.
  • Oligosaccharide - A substance which is a polymer built primarily from sugar-like monomers.
  • Oligonucleotide - A substance which is a polymer built primarily from nucleotide-like monomers.
  • Other - A substance which is not covered by the categories above.
So, a consistent, semantically useful description of a specific drug is constructed from a combination of Drug_Type_Subclass, Drug_Type, and Drug_Class.

For example:

Sildenafil is a "synthetic small molecule therapeutic"
Abciximab is a "monoclonal antibody biological therapeutic".
Vitamin D3 is a "natural product-derived small molecule supplement".
Ioflupane 123I is a "synthetic small molecule imaging agent"

 Any feedback, pointers to any existing classifications/taxonomies, etc. would be very welcome.

Parts 2, 3 and 4 for this Drug taxonomy will be posted shortly.

Wednesday, 2 March 2011

New Drug Approvals 2011 - Pt. VI Roflumilast (DalirespTM)

ATC code: R03DX07

On February 28th, 2011, the FDA approved Roflumilast (tradename:Daxas tradename:Daliresp NDA 022522) for the treatment of patients with chronic obstructive pulmonary disease (COPD) a chronic and serious disease involving restriction of full lung function. The narrowing of airways of COPD is irreversible, and follows inflammation in the lung, believed to be linked to environmental pollutants such as tobacco smoke, workplace dusts and urban air pollution. This inflammation causes structural damage to the delicate alveoli structures.

Roflumilast and an active metabolite, Roflumilast-N-Oxide, are selective Phosphodiesterase 4 inhibitors. The subfamily of Type 4 Phospodiesterases comprises four distinct members, PDE4A, -4B, -4C, and -4D (Uniprot:P27815, Q07343, Q08493, Q08499, respectively, all are very closely related enzymes containing a characteristic cyclic nucleotide diesterase catalytic domain Pfam:PF00233). These in turn occur in different splicing isoforms with tissue specific expression, many of them in the lung. Phosphodiesterase 4 catalyzes a reaction transforming cyclic 3'-5'-adenosine monophosphate (cAMP, ChEBI: 17489) into adenosine 5'-monophosphate (AMP). Roflumilast has an IC50 against PDE-4 of ca. 2nM, affinities against the PDE4A, PDE4B, and PDE4D isozymes are all similar, whereas affinity against the PDE4C isozyme is ca. 5 fold lower. The exact mechanism by which Roflumilast reduces the risk of COPD exacerbations is not known, but it is believed that an increase in cAMP levels in lung cells attenuates the abnormal inflammation process associated with COPD. In clinical trials, it was observed that the numbers of specific types of immune cells - eosinophils and neutophils - were reduced by 31% and 42% after 4 weeks of treatment with Roflumilast.

Roflumilast ( IUPAC: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide InChI: 1S/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24) SMILES: FC(F)Oc1ccc(cc1OCC2CC2)C(=O)Nc3c(Cl)cncc3Cl Chemspider:395793 ChEMBL:193240) is a synthetic small molecule drug containing no chiral centers. It has a molecular weight of 403.2 Da and calculated LogP of 4.4. Roflumilast has 4 hydrogen bond acceptors and 1 hydrogen bond donor and therefore fully complies with Lipinski's rule of five.

The structure of a number of phosphodiesterase enzymes are known, including a number of PDE4 isoforms, a typical complex of PDE4D with an inhibitor is PDBe:1y2k

Roflumilast's oral bioavailability (at the recommended dose of 500 ug) is approximately 80% and the volume of distribution (Vd) is about 2.9 and a clearance (CL) of 9.6 Roflumilast is transformed into an active metabolite, Roflumilast-N-oxide via a metabolic route involving cytochromes CYP1A2 (Uniprot: P05177) and CYP3A4 (Uniprot: P08684). It is the only metabolite observed in humans at relevant plasma concentrations. In-vitro inhibition of Phosphodiesterase 4 by the active metabolite is three times less potent compared to the parent compound. However, its plasma AUC is about 10-fold greater than the plasma AUC of Roflumilast.  Maximum plasma concentrations CMAX of Roflumilast and Roflumilast-N-oxide are reached after 1 hour and eight hours, respectively.  Plasma protein binding (ppb) of the dosed drug and the active metabolite is 99% and 97% respectively. Roflumilast is eliminated primarily through the urine and the drug's half life after oral administration is 17 hours and 30 hours for Roflumilast-N-oxide.

Roflumilast is administered once daily as an oral tablet containing 500 ug of active ingredient (equivalent to 1.2 umol).

The full prescribing information can be found here.

Roflumilast was approved by the European commission in 2010 and is marketed in Europe as Daxas. In the US, Roflumilast will be marketed by Forest Pharmaceuticals under the trade name Daliresp (product website).

EIPOD Applications for 2011 closing soon

The deadline for applications for the 2011 intake for EIPODs (interdisciplinary postdoc fellowships within EMBL, funded by EMBL and Marie Curie Actions) is approaching soon - 20th March 2011 to be specific. There are lots of interesting predefined projects, but also the opportunity to define your own collaborative project between EMBL faculty in different units.

The ChEMBL group are involved in two predefined projects 1) NGS methods for natural product profiling/discovery and 2) text mining approaches for clinical candidate discovery from the literature.

New Drug Approvals 2011 - Pt. V - Azilsartan Medoxomil (EdarbiTM)

partial ATC code: C09CA

The most recent FDA drug approval is Azilsartan Medoxomil, approved on February 25th (NDA 200796). Azilsartan Medoxomil (research code: TAK-491; tradename: Edarbi) is an angiotensin II receptor blocker prodrug indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents. Hypertension is a medical condition in which the blood pressure in the vessels is too high, and can lead to kidney failure, stroke, myocardial infarction (heart attack), aneurysm, and many other pathologies. The renin-angiotensin system is a key regulator of blood pressure; Angiotensin is an hormone system that regulates the blood pressure and the fluid balance. The short peptide Angiotensin II is the principal agent of this system, and is responsible for vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.

Azilsartan (ChEMBL: ChEMBL57242; PubChem: CID9825285; Chemspider: 8001032), the bioactive ingredient of the prodrug Azilsartan Medoxomil, is a selective AT1 subtype angiotensin II receptor (ChEMBL: ChEMBL227; Uniprot: P30556) antagonist and exerts its therapeutic effects by selectively blocking the binding of angiotensin II to the AT1 receptor in tissues, such as vascular smooth muscle and the adrenal gland. Angiotensin receptors are a class of G protein-coupled receptors (GPCR) that belong specifically to the family of rhodopsin-like receptors and in which the drug binding occurs at a well defined site within the ligand-binding domain (PFAM: PF00001). A second angiotensin receptor is also known - AT2 angiotensin II receptor (ChEMBL: CHEMBL4607; Uniprot: P50052) which is broadly expressed and suggested to mediate effects such as inhibition of cell growth, fetal tissue development, modulation of extracellular matrix, neuronal regeneration, apoptosis, cellular differentiation. AT2 angiotensin II receptor is not known to be associated with cardiovascular homeostasis and, moreover, Azilsartan has more than 10k-fold greater affinity for the AT1 receptor (with an IC50 of 2.6 nM for human AT1 receptor) than for the AT2 receptor. Also, Azilsartan does not significantly bind or block other receptors or ion-channels known to be involved in cardiovascular regulation.
>sp|P30556|AGTR1_HUMAN Type-1 angiotensin II receptor OS=Homo sapiens GN=AGTR1 PE=1 SV=1

Several treatments for hypertension are already in the market and these include, not only treatments with other angiotensin II receptor antagonists, such as Olmesartan Medoxomil (approved in 2002; tradename: Benicar), but also treatments with ACE inhibitors (e.g. Enalapril, approved in 1985; tradename: Vasotec), alpha-blockers (e.g. Prazosin, approved in 1976; tradename: Minipress), beta-blockers (e.g. Nebivolol, approved in 2007; tradename: Bystolic), calcium channel blockers and direct renin inhibitors (e.g. Aliskiren, approved in 2007; tradename: Tekturna). The -sartan USAN/INN stem covers angiotensin II receptor antagonists; other approved -sartan drugs from the C09CA ATC class include Candesartan, Eprosartan, Irbesartan, Losartan, Tasosartan, Telmisartan, and Valsartan. Sartans are often dosed with other antihypertension medications as a combination therapy.

Azilsartan Medoxomil (IUPAC: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-3-[[4-[2-(5-oxo-1-oxa-2-aza-4-azanidacyclopent-2-en-3-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate; SMILES: O=C(C1=C2C(N=C(OCC)N2CC3=CC=C(C4=CC=CC=C4C(N5)=NOC5=O)C=C3)=CC=C1)OCC6=C(C)OC(O6)=O ) has a molecular weight of 568.53 Da (606.62 Da for the potassium salt), has 1 hydrogen bond donor, 10 hydrogen bond acceptors, an AlogP of 5.3, a polar surface area of 139.6 Å2 and 10 rotatable bonds, which makes the molecule very flexible. Azilsaratan Medoximil does not contain any chiral centers, and as the active drug azilsartan, the physicochemistry will be dominated by the negatively charged carboxylic acid. Azilsartan medoximil is a synthetic small molecule drug.

Azilsartan Medoxomil is available for oral use as tablets. Each tablet contains 40 mg and 80 mg of Azilsartan Medoxomil. At the 80 mg dose level used in Edarbi, the daily molar dose is 140.7 µmol. Azilsartan Medoxomil is hydrolyzed to Azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan is relatively poorly absorbed (60% bioavailability), a volume of distribution (Vd) of approximately 16 L and a high plasma protein binding of >99%. Azilsartan is metabolised, mainly by CYP2C9, to two primary metabolites: a major metabolite formed by O-dealkylation, and a minor metabolite, formed by decarboxylation. These metabolites do not contribute to the pharmacologic activity of Azilsartan Medoxomil. Azilsartan Medoxomil is recovered in both feces (55%) and urine (42%), with 15% of the dose being excreted in urine as Azilsartan. The elimination half-life (t1/2) of Azilsartan is ca. 11 hours and the renal clearance (CL) is ca. 2.3 mL.min-1.

Azilsartan Medoxomil has a black box warning - and should not be used in pregnancy.

The full prescribing information can be found here.

The license holder is Takeda Pharmaceuticals America, Inc. and the product website is

Papers: Probing the links between in vitro potency, ADMET and physicochemical parameters

We are collaborators on a paper just published in Nature Reviews Drug Discovery, investigating the relationship of in vitro and physicochemical data and ADMET properties, as you will imagine, a lot of the underlying data for this work and analysis came from the ChEMBL database. There is quite a lot of new stuff in there...

%J Nature Reviews Drug Discovery
%V 10
%P 197-208
%D 2011
%O doi:10.1038/nrd3367
%T Probing the links between in vitro potency, ADMET and physicochemical parameters
%A M.P. Gleeson
%A A. Hersey
%A D. Montanari
%A J. Overington

ChEMBL RESTful Web Service API

We are pleased to announce the release of the ChEMBL RESTful Web Service API (application programming interface). The first release provides the functionality to support programmatic retrieval of ChEMBLdb compound, target, assay, and bioactivity data. In the coming weeks and months we will extend the feature set of the REST API to support:
  • Searching of compounds with SMILES, InChI keys, including substructure and similarity searches
  • Searching of targets by protein identifiers
  • Retrieval of results in JSON format
We have provided a documentation page that describes the API functionality in more detail and also describes how to get started with using our java client to access API:

Sample urls:
As always, you're feedback and suggestions for improving the API are most welcome. Please e-mail:

Update: In answer to an email question, the API is secure, runs under https: (http: calls will automatically be redirected automatically). The usual EBI terms of use apply to these services.