ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Friday, 29 July 2011

Meetings: SMR Recent Disclosures of Clinical Candidates

One of the best UK meetings I try to go to is the annual Society of Medicines Research (SMR) meeting on recent clinical candidates. This year, it is being held on Thursday 8th December 2011, the the NHLI in London, further details are here. Compounds covered include: OSI-906, AZD-4547, fostamatinib, POL-7080, and AFQ-056, amongst others.

Monday, 25 July 2011

Internship - Scientific Data Visualisation

We are looking for an intern for one month to design a new poster on drugs and their targets. We published a poster a few years ago, and now we want to make a new poster, built around pharmacological action and drug types. We are looking for someone with good aesthetic judgement, ideally a long-standing interest in scientific data visualisation and experience is network visualisation using tools such as Cytoscape. Familiarity with Adobe Illustrator on Mac OsX is essential. If you are interested, please get in touch.

The EMBL-EBI pays a standard stipend to all interns.

Friday, 22 July 2011

New Drug Approvals 2011 - Pt. XXIII Ticagrelor (BrilintaTM)

ATC Code: B01AC24
Wikipedia: Ticagrelor

On July 20th, the FDA approved Ticagrelor (Tradename: Brilinta; Research Code: AZD-6140, NDA 022433), a purinergic receptor P2Y12 platelet antagonist indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).

Acute coronary syndrome is often the initial presentation of an individual manifesting coronary artery disease (CAD). ACS can present as unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction. Typically, ACS begins with the rupture or erosion of a vulnerable plaque in a coronary artery, which results in the exposure of elements under the endothelial layer, such as collagen or von Willebrand factor, to circulating blood. These ligands trigger a series of responses, including platelet adhesion, activation, and aggregation.

Ticagrelor reduces the thrombotic risk in ACS by blocking the P2Y12 receptor on the platelet surface. This drug is the first reversible drug for the Purinergic receptor P2Y12, and prevents the binding of ADP by inducing a reversible conformational change. It is thus an allosteric antagonist. Inhibition of the signal transduction results in reduced exposure of fibrinogen-binding sites to the GP IIb/IIIa receptor and thereby impairment of platelet aggregation. Similarly to other approved drugs to treat ACS, such as Prasugrel (Tradename: Effient; ChEMBL ID: CHEMBL1201772) and contrary to clopidogrel (Tradename: Plavix; ChEMBL ID: CHEMBL1771) and ticlopidine (Tradename: Triclid (Discontinued); ChEMBL ID: CHEMBL833), ticagrelor is not a pro-drug, although its active metabolite (AR-C124910XX) has a comparable potency.

Purinergic receptor P2Y12 (Uniprot accession: Q9H244; ChEMBL ID: CHEMBL2001; OMIM: 609821) is a Rhodopsin-like receptor and therefore it is a member of the G-protein coupled receptor 1 family. The sequence of P2Y12 is:


There are no known 3D structures for this protein, but there are now several relevant homologous structures of other members of the family (see here for a current list of rhodopsin-like GPCR structures).

The -grel- or -grel USAN/INN stem covers primarily platelet P2Y12 receptor antagonists. Ticagrelor is the first reversible inhibitor of this class, and ticlopidine, clopidogrel and prasugrel all bind irreversibly to P2Y12. Other compounds in this class in late stage clinical development/registration include Portola Pharmaceuticals' elinogrel (Research code: PRT 060128), The Medicines Company's cangrelor (Research code: AR-C69931XX), and the Inspire Pharmaceuticals' regrelor (Research code: INS50589). Others at earlier stages of development include Arena Pharmaceuticals' temanogrel (Research code: APD791).

Ticagrelor (IUPAC: (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; SMILES: CCCSC1=NC2=C(C(=N1)N[C@@H]3C[C@H]3C4=CC(=C(C=C4)F)F)N=NN2[C@@H]5C[C@@H]([C@H]([C@H]5O)O)OCCO; PubChem:9871419; Chemspider:8047109, ChEMBLID: CHEMBL398435, Standard InChI Key:OEKWJQXRCDYSHL-FNOIDJSQSA-N) has a molecular weight of 522.6 Da, contains 4 hydrogen bond donors, 8 hydrogen bond acceptors, and has an ALogP of 2.37. Ticagrelor contains six defined stereocenters. Ticagrelor is a cyclopentyl-triazolo-pyrimidine and these agents are relatively resistant to enzymatic degradation by ectonucleotidases. Ticagrelor has clear structural resemblance to adenosine, the endogenous ligand for P2Y12, we have classified it as a natural product-derived small molecule drug.

Ticagrelor is available as an oral film-coated tablets of 90 mg, and the recommend daily dose is 180 mg (equivalent to 34.4 umol). It has an apparent volume of distribution of 88 L and its mean absolute bioavailability is 36% (range 30%-42%). Absorption of ticagrelor occurs with a median tmax of 1.5 h, and the formation of its active metabolite occurs with a median tmax of 2.5 hr. Both compounds are extensively bound to human plasma proteins (>99%). The mean plasma half-life (t1/2) is approximately 7 hours for ticagrelor and 9 hr for the active metabolite.

Ticagrelor is mainly metabolised by CYP3A4 and to a lesser extent by CYP3A5; therefore, other therapeutic agents that inhibit or induce these enzymes may alter their therapeutic effect or lead to adverse DDIs. In vitro metabolism studies demonstrate that ticagrelor and its active metabolite are inhibitors of the P-gp transporter. Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor.

Ticagrelor has been issued with a black box warning because, like other antiplatelet agents, it can cause potentially fatal bleeding.

The license holder for Ticagrelor is AstraZeneca, and the full prescribing information can be found here. Ticagrelor was approved in the EU in 2010 and is commercialised under the tradename Brilique. The European SPC can be found here.

Wednesday, 6 July 2011

New Drug Approvals 2011 - Pt. XXII Indacaterol Maleate (ArcaptaTM)

ATC Code: R03AC18

On July 1, the FDA approved indacaterol maleate (NDA 022383) for the long-term 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. Indacaterol maleate is administered as an aerosol through a dry powder inhaler and carries a boxed warning for asthma-related death and is not indicated for the treatment of asthma.

The active ingredient of indacaterol maleate is indacaterol (ChEMBL: 1095777) an agonist of the beta-2 adrenergic receptor (Uniprot: P07550, ChEMBL: 210) with measured EC50 of 11nM. Indacaterol exerts its effect through activation of the beta-2 adrenergic receptor, leading to smooth muscle relaxation and a widening of bronchioli in the lungs. Activation of the beta-2 adrenergic receptor stimulates the intracellular adenyl cyclase and increases cAMP levels, which in turn leads to a reduction of the level of calcium ions inside smooth muscle cells. Other long acting beta-adrenoceptor agonists (LABA) such as salmeterol, formoterol and bambuterol entered the market during the 1980s. The duration of action of these earlier compounds is 12 hours, while for indacaterol it is 24 hours.

Multiple crystal structures of the beta-2 adrenergic receptor now exist (PDBe: 2R4R, 2R4S, 2RH1, 3D4S, 3KJ6, 3NY8, 3NY9, 3NYA, 3P0G, 3PDS), a nano-body stabilized structure of the receptor in its activated form is shown below (PDBe: 3p0g).

Indacaterol (IUPAC: (R)-5-(2-((5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino)-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, SMILES: CCc1cc2CC(Cc2cc1CC)NC[C@H](O)c3ccc(O)c4NC(=O)C=Cc34 , InChI: 1S/C24H28N2O3/c1-3-14-9-16-11-18(12-17(16)10-15(14)4-2)25-13-22(28)19-5-7-21(27)24-20(19)6-8-23(29)26-24/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29)/t22-/m0/s1, ChemSpider: 5293751, ChEMBL: 1095777) is a is a synthetic small molecule drug with one chiral center. It has a molecular weight of 392.5 Da and calculated LogP of 3.93. Indacaterol has 4 hydrogen bond acceptors and 4 hydrogen bond donors and therefore fully complies with Lipinski's rule of five. The picture below shows both the active ingredient, indacaterol, and maleate.

The USAN stem name -terol indicates that indacaterol is a phenethylamine derivative bronchodilator. Other -terols include salmeterol, formoterol, bambuterol, vilanterol, milveterol and levalbuterol.

Indacaterol's bioavailability after inhalation is (at the recommended dose range of 75-150 µg) is 43-45% and the volume of distribution (Vd) is between 2.36 and 2.56 and a clearance (CL) of about Steady-state of Indacaterol levels is reached within 12 to 15 days. Plasma protein binding (ppb) of the dosed drug is 95.1-96.2%. Excretion of indacaterol is mainly through the fecal route, either as the parent compound (54% of the dose) or hydroxylated metabolite (23% of the dose).

Indacaterol maleate is administered once daily as an aerosol containing  75-150 µg of active ingredient from a powder inhaler.

The full prescribing information can be found here.

Indacaterol maleate was approved by the European commission in 2009 and is marketed in Europe as Onbrez. In the US, indacaterol maleate will be marketed by Novartis under the trade name Arcapta. 

Tuesday, 5 July 2011

New Drug Approvals 2011 - Pt. XXI Rivaroxaban (XareltoTM)

ATC code: B01AX06

On July 1st, FDA approved Rivaroxaban (trade name: Xarelto, Research code: BA-59-7939, NDA 022406), an anti-coagulant to prevent deep vein thrombosis (DVT) in patients with knee or hip replacement surgery. Rivaroxaban is the first orally applied direct inhibitor of Factor Xa (FXa), a key regulatory of the coagulation cascade. In DVT, a blood clot is formed which can dislodge and travel to the lungs, causing pulmonary embolism which can be potentially fatal.

Factor Xa (EC number, UniProt ID P00742, OMIM 613872) is a serine endopeptidase, cleaving prothrombin into its active form, thrombin, which then activates further downstream factors which ultimately lead to platelet activation and fibrin formation, clotting the damaged blood vessels. The sequence of Factor X is

>Factor X

Factor X itself is synthesized as an inactive precursor, and is further processed into a mature form, consisting of a light and an "activated" heavy chain (=FXa, residues 235-488, bold in the above sequence, carrying a trypsin-like domain, Pfam PF00089) (green and red in the below picture, respectively). There is a plethora of experimentally solved structures available for FXa, and also a holostructure of FXa in complex with Rivaroxaban, PDBe:2w26.

Rivaroxaban (ChEMBL ID 198362, ATC code B01AX06, PubChem CID 6433119) has molecular weight of 435.9 Da, an ALogP of 1.8, 5 rotatable bonds, 6 hydrogen bond acceptors, 1 hydrogen bond donor, and is thus fully Rule-of-Five compliant. It is dosed as a pure (S)-enantiomer. Canonical Smiles, Smiles=Clc1ccc(s1)C(=O)NC[C@H]2CN(C(=O)O2)c3ccc(cc3)N4CCOCC4=O, Standard InChi, InChI=1S/C19H18ClN3O5S/c20-16-6-5-15(29-16)18(25)21-9-14-10-23(19(26)28-14)13-3-1-12(2-4-13)22-7-8-27-11-17(22)24/h1-6,14H,7-11H2,(H,21,25)/t14-/m0/s1. Rivaroxaban is known to have a sub-nanomolar (0.7 nM) IC50 to the active site of human FXa.

Xarelto is administered orally as a 10 mg tablet once daily for 12 or 35 days (after knee/hip replacement surgery, respectively), yielding ~23 umol of active substance per single dose. Most relevant risks connected to Xarelto treatment are serious and fatal bleeding.

It has been given a boxed warning for spinal/epidural hematoma in surgical settings. It has not been tested in pregnant women, nursing mothers, or pediatric settings; majority of participants in clinical trials were 65 years and over, and the efficacy of Xarelto in the elderly was found to be similar to that seen in younger patients. The effect of Xarelto lasts 8-12 hours, but FXa activity stays depleted during 24 hours, so a once-daily dose is sufficient.

It has high (80-100%) bioactivity and is rapidly absorbed, reaching Cmax at 2 to 4 hours. Its volume is distribution is Vss=50 L. Little metabolism is observed for rivaroxaban, with the majority of the dose excreted unchanged.

The USAN/INN name stem, -xaban of rivaroxaban, designates a FXa inhibitor. Alternative anticoagulants, inhibiting FXa indirectly, include Heparin (ChEMBL ID 526514), an activator of Antithrombin, which itself is a FXa inactivator; Warfarin (ChEMBL ID 1464), a vitamin K antagonist, vitamin K being required for FXa biosynthesis. However, numerous other direct FXa inhibitors are currently being developed, e.g. Apixaban (BMS-562247-01, ChEMBL ID 231779), Betrixaban (PRT-054021, ChEMBL ID 512351), Edobaxan (Du-176b), Eribaxaban (PD-348292), Fidexaban (ZK-807834), Otamixaban (XRP-0673), YM-150, YM-466, Letaxaban (TAK-442), and GW-813893.

Xarelto has been developed by Bayer Schering AG. In US, it will be marketed by Janssen Pharmaceuticals, Inc.

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