The ChEMBL-og

We have had a couple of mails about the exclusion of AbobotulinumtoxinA (aka Dysport) as a new NME in some of our analyses of drugs for 2009. This is a subtle case, and our treatment of AbobotulinumtoxinA is as follows - but basically it is not an NME. Recently the FDA required that, due to the non-interchangeability, and potential safety issues of Botulinum Toxin A products from different manufacturers, that differing non-proprietary names were required for these products, despite the fact that nominally they contain the same active ingredient (in this case a large protein therapeutic). So Botox, marketed by Allergan, now uses the non-proprietary name onabotulinumtoxinA, while for Dysport (approved during 2009) from Ipsen, uses the non-proprietary name abobotulinumtoxinA. Since they essentially just differ by manufacturer, and not by active ingredient, we have not considered Abobotulinum toxin as being a new NME approval.

We're mopping up a few drug approvals from 2009 we have not yet covered yet as monographs... Approved on September 8th 2009 was Bepotastine Besilate, marketed under the trade name Bepreve. Bepotastine is a topical, selective and non-sedating histamine (H1) receptor antagonist indicated in the treatment of itching associated with allergic conjunctivitis. Through the H1 binding, Bepotastine has broad range of anti-inflammatory effects - a stabilizing effect on mast cells, inhibition of eosinophil migration and interleukin-5 (IL-5) , leukotriene B4 (LTB4) and platelet activating factor (PAF) release. Bepotastine has been previously approved in Japan, under the trade name Talion, for allergic rhinitis (2000) and urticaria and skin pruritus (2002). Bepotastine is a chirally pure, synthetic small molecule drug (Molecular Weight 388.89 g.mol-1 for Bepotastine itself and 547.06 g.mol-1 for the dosed besilate salt), is Rule-of-Five compliant and is delivered as an ophthalmic sol...

A brief note, really just a picture of a table of the New Molecular Entities of 2009 - there will undoubtedly be a few more approved this year, but this is the story so far. 24 New NMEs; of which 5 are biologicals, 5 are Natural Product derived, 14 are synthetic small molecules. 12 of the drugs have a black box warning at launch. 13 of the NMEs are orally dosed, and 13 pass the Rule of Five. Now back to thinking about EU grants.....

The first approval of the last month of 2009 is Ecallantide (trade name Kalbitor), approved on December 1st. Ecallantide, previously known by the research code DX-88, is a human plasma kallikrein ( P03952 ) inhibitor indicated for treatment of acute attacks of Hereditary Angioedema (HAE) in patients 16 years of age or older. HAE is a rare genetic disorder, giving the carrier low levels of C1-esterase inhibitor (C1-INH) activity and inherited as an autosomal dominant trait. C1-INH is the major endogenous inhibitor of plasma kallikrein, and functions to regulate activation of the complement system and also the intrinsic coagulation (or 'contact system' pathway). One critical aspect of this system is the conversion of High Molecular Weight kininogen (HMWk) to the nona-peptide bradykinin by the trypsin-like serine protease - plasma kallikrein. During HAE attacks, disregulated activity of plasma kallikrein result in excessive bradykinin generation; bradykinin is a potent...

Approved on November 5th 2009 was Romidepsin (trade name Istodax). Romidepsin, previously known by the research codes FK-228, FR-901228 and NSC-630176, is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. CTCL is a slow-growing cancer of infection-fighting white blood cells called T-lymphocytes . Romidepsin binds directly to the HDAC active site blocking substrate access. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. Romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of cancer cells. Romidepsin is the fourth drug to be approved for CTCL, after Vorinostat (trade name Zolinza), Bexarotene (trade name Targretin) and Denileukin Difitox (trade name Ontak). Vorinostat is a small-molecule drug which also inhibits HDACs,...

The latest approval this month, on October 26th, was Ofatumumab (trade name Arzerra). Ofatumumab is a CD20 -directed cytolytic monoclonal antibody indicated for the treatment of patients with refractory chronic lymphocytic leukemia (CLL) who have inadequately responded to both Fludarabine and Alemtuzumab. CLL is characterized by an abnormal proliferation of lymphocytes so-called B-cells . B-cells originate in the bone marrow and are involved in fighting infection. In CLL, the DNA of a B-cell is damaged and so it can not produce antibodies in order to fight infection. Moreover, they grow out of control and accumulate in the bone marrow and blood. Ofatumumab is an IgG1k human monoclonal antibody which binds specifically to both the small and large extracellular loops of CD20. CD20 is a non-glycosylated phosphoprotein expressed on normal B lymphocytes and on B-cell CLL. Since it is not shed from the cell surface, it allows for antibody binding, and when so, it sends a signal acros...

Another drug onto the market this month is Pazopanib, marketed as Votrient, which was approved on October 19th. Pazopanib Hydrochloride (previously known as GW-786034-B) is the sixth drug to be approved for kidney cancer, after Sorafenib (trade name Nexavar), Sunitinib (trade name Sutent), Temsirolimus (trade name Torisel), Everolimus (trade name Afinitor) and Bevacizumab (trade name Avastin). Sorafenib and Sunitinib are both orally dosed small molecule inhibitors of tyrosine protein kinases, which interfere with tumor growth by inhibiting angiogenesis as well as tumor cell proliferation; Temsirolimus and Everolimus are specific inhibitors of mTOR ( mammalian target of rapamycin ), a serine-threonine kinase, which interfere with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells; Bevacizumab is a monoclonal antibody that recognizes and blocks VEGF, which is a chemical signal that stimulates angiogenesis. Pazopanib is a small-molecule dru...

Also approved on September 25th was Pralatrexate (tradename Folotyn). Pralatrexate is the first drug approved for the treatment of Peripheral T-Cell Lymphoma (PTCL) , an aggressive form of non-Hodgkins lymphoma . Lymphoma is a cancer that begins in the lymphocytes of the immune system. PTCL is a rare disease, occurring in around 9,500 patients each year in the United States. Pralatrexate, also known as PDX, is a folic analog that competitively inhibits dihydrofolate reductase (DHFR). Since Pralatrexate blocks the use/function of a metabolite, it is also an antimetabolite . Pralatraxate has high affinity for the folate transporter SLC19A1 (also known as RFC-1), and so is an example of a drug that is 'actively transported', and is also a substrate for polyglutamation by the enzyme folylpolyglutamate synthase (FPGS). Once polyglutamated Pralatrexate has a prolonged intracellular half-life, giving prolonged action in malignant cells. Pralatrexate is related to several other ...

Recently approved by the FDA, on September 25th 2009, was Ustekinumab, marketed under the trade name Stelara. Ustekinumab, previously known as CNTO-1275, is a first-in-class injectable biological drug blocking signalling of two distinct interleukins ( IL-12 and IL-23 ) and is indicated for the treatment of adults with moderate to severe plaque psoriasis . Psoriasis (ICD-10: L40 ) is a complex autoimmune disease, typically leading to the formation of scaly red or silvery-white plaques on the skin. Another drug with the same mechanism as Ustekinumab (blocking IL-12 and IL-23 signalling) is ABT-874, ABT-874 is currently still in clinical trials. Ustekinumab is dosed as a subcutaneous injection given at weeks 0 and 4, followed subsequently by every-12-week maintenance dosing. The recommended starting dose of is 45 mg for patients weighing 100 kg or less, and 90 mg for patients weighing more than 110 kg (the 45mg dose corresponds to a 0.31 umol dose). Ustekinumab is is a human IgG1қ mo...

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...

The next approval for this year, on August 21st, was Vigabatrin (trade name Sabril). Vigabatrin (previously known by the research code MDL-71,754) is an antiepileptic drug indicated as a monotherapy for pedriatic patients 1 month to 2 years of age with infantile spasms (IS) and as an adjunctive therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments. Vigabatrin has previously been approved in the UK, Mexican, Canadian and Danish markets. Vigabatrin is the first therapy approved for the treatment of IS and a new option as add-on therapy for the adults with CPS. Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T) , the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA ; blockade of GABA-T leads to increased levels of GABA in the central nervous system. This enzyme can also be irreversible inhibited by Gabaculine , a naturally occurring ...

We have made a few changes to the icon set we use for the ChEMBL-og New Drug Monographs , we will also use these (or variants thereof) in some of our other web interfaces. The changes were prompted by some of the things we wished we had included from the start. An example icon is below. Which is a synthetic small molecule drug, is rule of five compliant, is topically dosed, is dosed as a single enantiomer, and has a boxed warning. The various components mean Drug class this can either be Synthetic small molecule Natural product-derived small molecule Peptide/protein Protein: Monoclonal antibody Protein: Enzyme Oligonucleotide Oligosaccharide. Rule of Five An image of the number five. This is either pass or fail - we fail a molecule if it fails to pass all the individual tests (usually people use fail one parameter ). We use XlogP (the same as used by PubChem) for the calculations and use 5.0 as a cutoff New target An image of a 'bullseye' target. This is either tru...

On the 14th August 2009 Asenapine (tradename Saphris) was approved for the acute treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. This class of psychiatric diseases are complex and carry a significant economic healthcare burden; approximately 24 million people worldwide are believed to suffer from schizophrenia, while ca. 67 million people are thought to suffer from bipolar I disorder. Asenapine (previously known by the research code Org-5222) is the one of a large class of drugs aimed at treating such diseases, and shows the typical broad spectrum of against a variety of receptor targets and a complicated mechanism of action, although such drugs are thought to primarily act through antagonism of D2 and 5HT2A receptors. To give some idea of the promiscuity (or polypharmacology) of Asenapine at various aminergic GPCRs, reported pKis are 5HT1A 8.6, 5HT1B 8.4, 5HT2A...

The latest FDA approval is Pitavastatin (trade name Livalo), approved on August 3rd. Pitavastatin is an HMG-CoA reductase inhibitor, indicated for the primary treatment of hypercholesterolemia (elevated levels of cholesterol in the blood) on patients unable to sufficiently lower their cholesterol levels by diet and exercise. Hypercholesterolemia is a very widespread and leads to serious cardiovascular disease in affluent and increasingly in developing societies. Pitavastatin (also known by the research code NKS-104) has been available in Japan since 2003 and is now the sixth statin to reach the U.S. market, after Lovastatin (trade name Mecavor), Pravastatin (trade name Pravachol), Fluvastatin (trade name Lescol), Atorvastatin (trade name Lipitor) and Rosuvastatin (trade name Crestor). All of these drugs are derived from the natural product Mevastatin from the fungus Penicillium citrinum . Like the other statins, Pitavastatin lowers the cholesterol levels by competitively in...

On the 31st July 2009 Saxagliptin (tradename Onglyza) was approved for the treatment of Type II diabetes - Type 2 Diabetes is also known as adult-onset diabetes, and also non-insulin-dependent diabetes melittus (NIDDM). It is the type of diabetes that is often associated with obesity, and so is an increasingly common disease/condition in our well-fed western and also developing world cultures. Saxagliptin (previously known by the research code BMS-477118) is the third orally-dosed Dipeptidyl peptidase-IV (or DPP-IV) inhibitor to market, and is in the same mechanistic class as other 'gliptins' - Sitagliptin (tradename Januvia) and Vildagliptin (tradename Galvus/Eucreas) which are both launched and also others such as Alogliptin (aka SYR322) and Linagliptin (aka BI-1356, and expected tradename Ondero), which are in late stage clinical trials. The DPP-IV drug class has had quite a complex development and commercial history, as web searches will readily show. Saxaglipti...

Another drug reaching the market this year is Dronedarone (trade name Multaq), approved on July 1st. Dronedarone is a antiarrythmic agent indicated to reduce the risk of cardiovascular hospitalization in patients with a history of heart rhythm disorders. The drug is approved to be used in patients whose hearts have returned to normal rhythm or who will undergo drug or electric-shock treatment to restore a normal heart beat. Dronedarone is an antiarrythmic agent of unknown detailed mechanism of action (specifically it does not fit into one of the existing Vaughn Williams classification scheme), but is known to be a multi-channel blocker that affects calcium, potassium and sodium channels and also has anti-adrenergic receptor activity. Dronedarone (previously known by the research code SR33589) is a relatively large small molecule drug (Molecular Weight of 556.8 g.mol-1 for Dronedarone itself, and 593.2 g.mol-1 for the HCl salt), highly lipophilic and practically insoluble in water. D...

The latest approval this year is Prasugrel (USAN), approved on July 10th under the trade name Effient. Prasugrel is a P2Y12 receptor platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention. Prasugrel is the third to market in the thienopyridine class of ADP receptors antagonists, after Ticlopidine (trade name Ticlid) and Clopidogrel (trade name Plavix). Prasugrel is a prodrug ; meaning that Prasugrel is not therapeutically active itself, but is metabolized in the body to give the pharmacologically active metabolite. Additionally, the metabolically activated form of Prasugrel irreversibly binds to its receptor - this means that it forms an unbreakable chemical bond to its target, again this is quite an unusual feature. Prasugrel is a small molecule drug (Molecular Weight of 343.4 g.mol-1 for Prasugrel itself and 409.9 g.mol-1...

Also approved this year is Benzyl Alcohol, under the trade name Ulesfia, approved on April 9th. Benzyl Alcohol has many uses, but it is now approved as a pediculicide, indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Benzyl Alcohol inhibits lice from closing their respiratory spiracles, causing the lice to asphyxiate. This is the first and only prescription medication that kills head lice by asphyxiation without potential neurotoxic side effects. Ulesfia is supplied as a topical lotion containing Benzyl Alcohol, 5%. Benzyl Alcohol is a small molecule drug (Molecular Weight of 108.1 g.mol-1), fully Rule-of-Five compliant, slightly lipophilic and partially soluble in water. Recommended administration and full prescribing information can be found here . The chemical structure is very simple, and probably does not warrant much useful disection and discussion. Benzyl Alcohol canonical SMILES: OCc1ccccc1 Benzyl Alcohol InChI: InChI=1/...

Also on the market this year is Besifloxacin Hydrochloride (USAN) which is marketed as Besivance, approved on May 28th. Besifloxacin is a fluoroquinolone antimicrobial indicated for the treatment of bacterial conjunctivitis, and competes against other fluoroquinolones for the ophthalmic treatment of bacterial infections. Besifloxacin has activity against Gram-positive and Gram-negative bacteria and acts through inhibition of both bacterial DNA gyrase and topoisomerase IV. Besifloxacin is known to be active against various Corynebacterium , Haemophilus , Moraxella , Staphylococcus and Streptococcus spp. Besifloxacin is a small molecule drug (Molecular Weight of 393.8 g.mol-1 for Besifloxacin itself, and 430.3 g.mol-1 for the HCl salt), is Rule-of-Five compliant and is delivered as an ophthalmic suspension. Besifloxacin has a plasma half-life is of 7 hours. Recommended dosage is one drop instilled in the affected eye(s) 3 times a day, four to twelve hours apart, for 7 days. The fu...

Another drug onto the market this year is Iloperidone (USAN) marketed as Fanapt, which was approved on May 6th. Iloperidone is an antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone displays broad polypharmacology, acting as an antagonist at dopamine D2 (Ki of 6.3 nM) and dopamine D3 (Ki of 7.1 nM), serotonin 5-HT2A (Ki of 5.6 nM), dopamine D4 (Ki 25 nM), 5HT6 (Ki of 43 nM), 5HT7 (Ki of 22 nM) and alpha-1 adrenergic receptor (Ki of 36nM) (phew!) and belongs to the general class of atypical antipsychotics . Lower affinities, but also probably relavent for the clinical pharmacology, are observed at the 5HT1A, D1 and H1 receptors). Iloperidone is a small molecule drug (Molecular Weight of 426.5 g.mol-1), is fully Rule-of-Five compliant, lipophilic and pratically insoluble in water and has good oral absorption (96% bioavailable). Iloperidone has a plasma half-life of 18 hours, a volume of distribution of 1,340-2,800L and plasma protein binding o...