• 2010 New Drug Approvals - Pt. III - Liraglutide (Victoza)
    ATC code: A10BX07

    Also approved in January is Liraglutide, on January 25th, under the trade name Victoza. Liraglutide, previously known as NN2211, is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. People with this type of diabetes are often overweight, have high blood pressure and/or cholesterol and become insensitive to insulin. Type 2 diabetes is the commonest form of diabetes, and is a major health problem in 'developed' economies. Liraglutide ATC code is A10BX07. 

    Liraglutide works by activating the GLP-1 receptor (GLP-1R), which in turn stimulates the adenylyl cyclase pathway leading to insulin release in the presence of elevated glucose concentrations. GLP-1R is a class-II GPCR (also known as secretin receptor family). Liraglutide is the second GLP-1 agonist approved for the treatment of type 2 diabetes, after Exenatide (marketed as Byetta), which reached the market in 2005. Other -glutides in development include Taspgolutide (R1583 or BIM-507) developed by Roche, and Abiglutide (a stabilized GLP-1 analogue fused to serum albumin) from GSK. Liraglutide is an engineered form of the natural human GLP-1 peptide (one amino acid difference to the major circulating form of GLP-1, GLP-1(7-37) - an arginine replaces a lysine at position 34), an additional modification is the addition of palmitic acid attached via a glutamic acid spacer at position 26. The molecular weight of Liraglutide is 3751.2 Da.

    Each standard dose contains 1.8mg of Liraglutide (equivalent to 480 nmol). Dosing is as a once daily subcutaneous (s.c.) injection. Liraglutide has a plasma half-life of ~13 hr (far longer than the ca. 2 min half life of the natural GLP-1 peptide). Slowing the fast degradation of GLP-1 is the basis of the therapeutic mechanism of the -gliptin class of DPP-IV inhibitors, e.g. Saxagliptin and Sitagliptin). The absolute bioavailability of Liraglutide, after s.c. dosing is 55%, and has high plasma protein binding > 98%. The volume of distribution Vd is 0.07L/kg, with a clearance of 1.2 L/h. Liraglutide has a boxed warning (risk of thyroid C-cell tumours). Victoza is marketed by Novo Nordisk and the product website is http://www.victoza.com.

  • 2010 New Drug Approvals - Pt. I - Tocilizumab (Actemra/RoActemra)




    The first FDA approval of this year is Tocilizumab, approved on January 8th, under the trade name Actemra. Tocilizumab is a first-in-class interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody drug, and is indicated for the treatment of rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Rheumatoid arthritis is a chronic and debilitating, systematic inflammatory disorder, which affects principally synovial tissues. Tocilizumab ATC code is L04AC07. Tocilizumab works by blocking the signalling of IL-6, an immune system soluble cytokine that is overproduced in patients with rheumatoid arthritis. Other biological therapies for RA include tumor necrosis factor-α (TNF-α) blockers (e.g, Golimumab), IL-1 blockers (e.g., Anakinra), monoclonal antibodies against B cells (e.g., Rituximab) and T cell costimulation inhibitors (e.g., Abatacept). However, all these act through binding to different target molecules. Others drugs with the same IL-6R binding mechanism as Tocilizumab are ALD518 and CNTO-136, which are currently reported to be in Phase II clinical trials. Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody of the immunoglobulin IgG1κ subclass. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) - mIL-6R is also known as CD126. Tocilizumab has a molecular weight of ca. 148 kDa, with a volume of distribution of ~6.4L, a linear clearance of ~12.5 mL/h and a half-life up to 13 days. The recommended starting dosage is ~4 mg/kg followed by an increase to ~8 mg/kg based on clinical response, administrated as a single intravenous drip infusion over 1 hour, every 4 weeks. Interestingly, Tocilizumab, via blocking cytokine signalling can affect expression levels of a wide variety of CYP450 drug metabolizing enzymes, leading to the potential for drug-drug interactions. The full prescribing information for Tocilizumab can be found here. Tocilizumab has a boxed warning (Risk of serious infections). Each light and heavy chain of Tocilizumab consists of 214 and 448 amino acids, respectively, and the four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. The license holder of Tocilizumab is Genentech, Inc. and the product website is www.actemra.com.

  • Minor revisions to Chembl interface

    Many thanks to the attendees on the Small Molecule Bioactivity Course at the EMBL-EBI last week. We have a big list of things to fix, a bigger list of things to think about, and despite thinking three weeks ago that we would never want to do the course again, are now looking forward to it again next year.

    We have made some minor interface changes, available at http://www.ebi.ac.uk/chembldb/index.php/

    Frr those of you waiting for the interface/database webinars, something will be announced soon...

  • FAQ: How do I get some advice on how to use chembl?

    The simplest way is to contact us at chembl-help@ebi.ac.uk.

  • FAQ: I've done some virtual screening using chembl, can you send me the compounds?

    We do not have physical samples of any of the compounds in chembl, so we cannot supply any samples to you. Sorry. If you want to obtain samples of chembl compounds you do have a number of options: 1) Often the underlying literature contains a synthetic route and reagents for the compounds, this greatly helps resynthesis. 2) About 5-10% of chembl compounds are reported to be available from compound vendors (for example, you could search databases such as the excellent ZINC to find available compounds). However, the turnover of stock from compound vendors is quite high, and often a significant fraction of compounds reported to be available for purchase will be out of stock when you want them.

  • 2010 New Drug Approvals - Pt. II - Dalfampridine (Ampyra)


    The second NME approval this year is Dalfampridine (trade name Ampyra), approved on January 22nd. Dalfampridine is a potassium channel blocker indicated to improve walking in adults with multiple sclerosis. Multiple sclerosis is a serious chronic disease that affects the central nervous system and in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring. The therapeutic mechanism of Dalfampridine is complex, has not been fully elucidated, but it has been shown to increase conduction of action potentials in demyelinated axons through inhibition of potassium channels, probably Shaker channels.

    Dalfampridine is a (very) small molecule drug (Molecular Weight 94.1 g.mol-1), fully Rule-of-Five compliant and soluble in water. Dalfampridine (also known as 4-AP) has good oral bioavailability (96% bioavailable), with a volume of distribution of 2.6 L/kg and low plasma protein binding. Excretion is mainly renal (95.9% of the dose recovered in urine) and mostly as the parent drug (90.3%). Dalfampridine metabolites are 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate (a sulphated form of the previous metabolite). These metabolites have no pharmacological activity on potassium channels. The elimination half-life of Dalfampridine is 5.2-6.5 hours. The maximum recommended dosage is 10mg twice daily (equivalent to a dose of 106uM) and full prescribing information can be found here. Dalfampridine chemical structure is 4-aminopyridine, a very simple unremarkable structure. 

    NAME="Dalfampridine" TRADEMARK_NAME="Ampyra"
SMILES="n1ccc(N)cc1"
InChI="InChI=1/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7)"
InChIKey="NUKYPUAOHBNCPY-UHFFFAOYAH"
ChemDraw=Dalfampridine.cdx

    The license holder is Acorda Therapeutics, Inc. and the product website is www.ampyra.com.
    
	  
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    Papers for Abstraction into Chembl...
    
	  	
	  	

    


    
We would be keen to hear of key SAR publications that people would like entered into chembl (if they aren't there already). Send us the PubMed id, and we'll add it to our list, and then see whether it is in scope (and budget!) of chembldb.
    

    
If we get sufficient input of this, we'll post the list of papers.
    
	  
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    SMR Meeting: Regenerative Medicine, Cambridge 11th March 2010
    
	  	
	  	

    

    The SMR run arguably the best series of UK-based drug discovery meetings - they're cheap, they are on one day and they attract great speakers, and they are pharma/biotech focussed. The next is 
    
Regenerative Medicine: A New Frontier for Therapeutic Intervention     to be held on the 11th of March, at Granta Park in Great Abington, just outside of Cambridge. Further details are on the SMR website
    
	  
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