Early Stage Drug Discovery Review (Lectures 1-4) PDF

Early stage drug discovery Drug Target identification and validation Screening and Lead compound identification Structure activity relationships I, II, and III Lecture 1- Early stage drug discovery Drug discovery pipeline Takes 6-10 years and $1.3 billion to develop a drug Why is DDP so...

Early stage drug discovery Drug Target identification and validation Screening and Lead compound identification Structure activity relationships I, II, and III Lecture 1- Early stage drug discovery Drug discovery pipeline Takes 6-10 years and $1.3 billion to develop a drug Why is DDP so expensive? ○ Start with many many potential drugs ○ Could get all the way to phase III clinical trials to find that drug doesn't work or is too toxic Drug development pathway Doesn’t always work in a linear fashion Drug Discovery outline 1. Choose a disease 2. Identify and validate drug target 3. Design in vitro bioassays 4. Identify a lead compound 5. Lead compound optimization→ target interactions 6. Lead compound optimization→ PK 7. Chemical and process development 8. Toxicological and safety tests 9. Patenting and regulatory affairs 10. Clinical trials Choosing a Disease Pharm industry = business→ $$$ Find a way to make money Find disease state where symptoms can be managed ○ Not looking for a cure→ bc then medication wouldn’t be used after the disease is cured Questions to be addressed ○ What population is affected by the disease? Small or large Money or no money ○ First world vs. third world ○ Do effective drugs already exist ○ Why would new drug be advantageous ○ Cure disease vs manage symptoms Top 10 Drugs Most drugs are treating long term, chronic conditions → lots of money 2012: * coming off patent*- after the date, new generic medications can be made 2013: # macromolecules (antibodies Drug doesn’t have to be a small molecule to be a top selling drug In this class we talk mostly about small molecules From 2014- 2020→ the same 5 macromolecules stay on the market as top 10 drugs Generic Drugs Patent lasts 20 years from the date you first file paperwork with the government After drug goes off patent→ generic drugs can be made Generic drug- identical to the name brand in “all ways that matter” ○ Bioequivalent- must work the same ○ Specific similarities are a moving target- dosage form, route of administration, performation, and intended use ○ Differences allowed include color, size, shape, additives, binders, and filling agents Companies look for any way to extend patent lifetime Cheaper to make because company didn’t spend the research time/money developing it  Name brand needs to decide if they want to lower price to be closer to generic Companies file patent before drug is approved ○ As soon as drug seems promising→ file patent ○ Early stage→ before clinical trials ○ This is so that if other companies catch wind of the drug, they can’t get their own patent Upward Trend- Age related Diseases associated with aging population ○ US life expectancy- 68 (1960) to 80 (2030) ○ Neurological (degenerative) and cancer People in general are living longer→ larger population of older people Ex. dementia, parkinson’s, Alzheimer’s (golden ticket drug) Downward Trend- Cardiovascular Cardiovascular disease is still the #1 cause of death in the US→ significant reduction in number of programs developing new medications There are already cheap, effective medications that have significantly decreased death rate ○ Statins- lower cholesterol (Lipitor) ○ Aspirin and Plavix- decrease blood clots ○ ACE inhibitors and Beta blockers- lower blood pressure Companies don’t want to spend a lot of money because there are already inexpensive medications available Torcetrapib Current statins (Lipitor) target HMG-CoA reductase→ the first step in cholesterol synthesis Cholesterol ester transferase (CETP)- transfers cholesterol from HDL (good cholesterol) to LDL (bad cholesterol) Inhibitors of CETP could work by itself or in combination with statins This was Pfizer’s plan after lipitor went off patent  Early clinical trials showed that combination increased HDL by 55-60% and decreased LDL by 50-60% Early clinical trials also showed evidence that torcetrapib raises blood pressure ○ Modest effect on blood pressure→ marginal importance compared to its potential lipid-modulating benefits Phase III trial → showed increased risk of death related to cardiac effects via unknown mechanism Can you do better than statins? Orphan Disease/Orphan Drug Orphan drug- treats a disease/disorder that affects a small portion of the population (