3 pages due by 20 hrs(pete)

3 pages (Only answers)

Ideation of GLP-1 receptor agonists

1.ABT-229

· The drug ABT-229 (alemcinal) failed to treat gastroparesis in diabetic patients in Phase 2 trials

· Summarize:

· At what receptor does it act, and what molecule is its natural endogenous agonist. What cells secrete this natural agonist? Google this.

· From the paper by Thielemans 2005, extract the EC50 (nM units!) for the natural endogenous agonist and for ABT-229 in a functional assay. Does ABT-229 seem potent enough for a human drug? Thielemans 2005

· Visit the IUPHAR GPCR page for the receptor: IUPHAR GPCR page

· Find out if it belongs to GPCR class A, B, or C.

· The first agonists at this receptor identified were antibiotics. What is the EC50 for azithromycin at this receptor? Does it seem potent enough for use as a drug?

· You want to do some research with this receptor and would like to have a potent antagonist. Identify the most potent one in the IUPHAR page for this receptor and report its name, (good) structure, and KB (nM units!)

· Find and show a good structure of ABT-229 (Google images is a good source)

· Why did ABT-229 fail in the clinic? (Read Tack 2001, and relevant part of Sanger 2013)

2.Learning about INN names

•What is an INN name and why do I care?

•Look at the WHO page showing the Lists of proposed and approved INN names: https://www.who.int/medicines/publications/druginformation/innlists/en/

•Please note that INN names are never capitalized unless they appear at the beginning of a sentence.

•As an example, find the proposed or approved INN entry for the kinase inhibitor dubermatinib

•Until recently WHO did not have a free search function

•Typically, you looked for the Lists containing the INN name using Google. It was difficult sometimes.

•This website may allow you to search for INN Lists by entering the INN name: https://extranet.who.int/soinn/

•Paste the dubermatinib entry on a paper, including all names and the structure (as an image)

•Also indicate from what INN List # you obtained the information, and whether it was the proposed or approved INN name List

3.Cost of drugs

Sales of an NCE start upon approval and while patent protection and SPC/PTE afford exclusivity.

•Typically, this exclusivity lasts 12 years. You can see why in this paper from your IP teacher:

•When exclusivity ends, generics can enter the market and sales of the innovator drug fall to (almost) zero in most cases (except biologicals).

•Your company developed an NCE that took a long time to bring to market and cost a lot of money. Assume it is necessary to obtain a revenue (gross sales) of $ 2.4 billion over those 12 years to recover the investment, cost of goods, operating costs, cost of capital & a suitable return on investment.

•Assume sales are equally divided over the 12 years. Sales per year should be $ 200 million. Your drug will not be used to treat a serious disease or an orphan indication.

•present the above premises and a table showing what would be the cost of the drug per patient per year of treatment if the number of patients treated is as in the table below.

•What are the consequences if your company can treat only 1000 patients per year?