Flashcards in Chapter 5 - Selecting a Drug Target Deck (25):
what makes a good drug?
1. singularly defined disease target
2. large potential market
3. molecular factors
-high specificity/ selectivity
-low toxicity/ side effect profile
when choosing a drug target, what is important about the disease choice?
1. unmet clinical need
2. return on investment
what is important about the drug target itself?
1. single gene product
2. single gene
3. single process
4. validated early on in the drug development process
give 3 examples of unmet medical needs
1. solid tumours
-TB/ HIV (developing world)
give examples of "disease mongering"
restless legs syndrome
social anxiety disorders
describe the nature of genetic targets.
1. usually single gene diseases
2. targets from HGP/ population studies
3. easily validatable
4. easily assayed (e.g. transgenic animals)
multifactorial diseases most common
variable nature of gene product (CF, HC)
variable frequency of abnormal gene
describe the nature of mechanistic targets
1. any diseases
2. targets from biological research
3. sometimes difficult to validate
4. more difficult to assay
disease modelling difficult
unpredictability of outcomes
give the three types of disease modelling
give the case history for peptic ulcer disease
(start with the disease)
1890s: Pavlov shows role of nerves in gastric secretion
1913: Henry Dale discovers histamine
1916: Polpielski shows histamine is a gastric secretagogue
1964: Black produces cimetidine after drug optimisation from burimamide as lead compound
give the case history for obesity (starting with the gene)
1994 discovery of leptin; hormone released by fat cells - secretion proportional to fat stores
-family discovered with a leptin gene mutation, affected individuals morbidly obese, treated with leptin infusion
-leptin infusion subsequently found to have no effect on obese people with normal leptin gene
-conclusion; some genetic therapies may only work for specific mutations
-major problem for now and in the future, huge market for anti-obesity drugs
give the case history for hypertension
(starting with the molecular target)
vascular muscle relaxation
cGMP secondary messenger
breaks down cGMP
-initially assayed activity of compounds on isolated aortic bands, then pure PDE5 from rat kidney
1986 Pfizer, UK: ANP potentiating molecules to treat hypertension
1988; noted that PDE5 highly expressed in vascular smooth muscle, platelet and absent from kidneys/
1989; developed lead compounds
1992 phase I; less efficacy than nitroglycerin, at high doses penile erection
1994; double-blind clinical trials, 300 patients 88% response rate, 39% placebo rate
1998; liscensing of sildenafil (viagra). 2.9 million US prescriptions in the first quater
give the case history for atherosclerosis
(starting with a molecular target)
CETP: Cholesterol ester transfer protein
-rare mutations leading to increased function of CETP have been linked to accelerated atherosclerosis
-a polymorphism of the CETP gene leading to lower serum levels, lower LDL, and higher HDL levels has also been linked to exceptional longevity
CETP inhibitor (Torcetrapib) made by pfizer:
good human toxicology
phase III trial enrolled from 2005 onward: torcetrapib + lipitor v placebo + lipitor
2006: 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin vs. taking atorvastatin alone. trial stopped
cost pfizer ~$800m
what benefit is there to target based drug discovery?
allows advances in biological reasearch to be rapidly translated into therapeutics
what makes target based drug discovery difficult
the biology can be unpredictable due to the unpredictability of complex systems
why does target based drug discovery make drug design more difficult
the requirement of proper validation of target disease models i.e "proof of principal" is impossible, leading to high attrition levels
name three "random" approaches to drug discovery
1. combinatorial chemistry
2. high throughput screening
what enzyme is used to metabolise ADMA to citrulline?
what is ADMA produced from?
what is the physioloigical function of DDAH?
inhibits blood vessell growth into a sponge model in vivo
what up regulates DDAH?
Where does DDAH-2 expression increase?
in hypoxic margin of MI
what up-regulates DDAH-2 expression?
what is the concequence of DDAH-2 over-expression?
increases VEGF expression and promotes "tube" formation
what is the possible use of a DDAH drug?