Drug discovery stages

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

In the drug discovery stage, suitable sources are explored. Sources of drug molecules can be natural, e.g. narcotic analgesic, morphine, from Papaver somnifemm (Poppy plant), synthetic, e.g. a popular analgesic and antipyretic, paracetamol, or semi-synthetic, e.g. semi-synthetic penicillins. 

I. DRUG DISCOVERY STAGE (STRUCTURE-ACTIVITY RELATIONSHIP AND COMPOUND SELECTION STAGE)... 

I. Drug Discovery Stage (Structure-Activity Relationship and Compound Selection Stage). 174... 

When an appropriate internal standard could not be found, it is sometimes possible to develop a method without an internal standard [19], especially for usage in early drug discovery stage where less strict criteria could be used. Nevertheless, efforts should be made to minimize the variations in sample extraction, LC separation, and... 

The metabolite characterization of a new chemical entity (NCE) in various drug discovery stages is crucial in assessment of the safety of a drug for human use [108,120-125]. The identification of metabolites may reveal the metabol-ically labile portions of a molecule in a particular drug series. This information can be used by the synthetic chemists to synthesize compounds that are less susceptible to metabolism and, consequently, have a lower elimination rate and a longer half-life. 

These passive obstacles to antibiotic action complicate treatment of infectious disease in the absence of highly accurate diagnostic tools to identify the infectious pathogen. Intrinsic resistance is problematic but is predictable and easily identihed in the preclinical drug discovery stages. As a result, the spectrum of susceptible microbial species is weh known before the compound enters the clinic. 

Their computational results have been referred to as the Rule of Five, and it had a major impact on drug discovery in the pharmaceutical industry. The Rule of Five was implemented early on in the drug discovery process for all the drug discovery stages, particularly medicinal chemistry design, to avoid a designed compound with potential absorption and permeability failure. 

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