Chapter 5 - Selecting a Drug Target Flashcards Preview

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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
-small molecule
-reversible effects
-correct PK
-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
2. infection
-TB/ HIV (developing world)
-antibiotic resistance
3. alzheimer's


give examples of "disease mongering"

erectile dysfunction
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

in vitro
in vivo
in silico


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
well tolerated
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
3. chance


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?

rentinoic acid


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?



what is the possible use of a DDAH antagonist?

anticancer drug