Drug development potency

Lead structure According to Valler and Green s definition a lead structure is a representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development program [12]. 

Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

Biological activity is not the only criterion required for drug development, as anyone who has been involved in this area is aware. Potency, toxicity, bioavailability, metabolic stability, and plasma half-life are only a few of the critical issues that must be addressed. Although satisfactory potency and spectrum activity had been achieved with WIN54954, which has been clinically evaluated, this compound lacked metabolic stability and consequently displayed a short half-life. 

Analytical methods are important not only in the development and manufacture of commercial biopharmaceutical drugs, they also play a vital role in the whole drug development life cycle. Drug discovery and preclinical research require development and application of analytical methodologies to support identification, quantitation, and characterization of lead molecules. It is difficult to perform a comparative potency assay on lead molecules if one does not know how much of each is going into the assay or how pure the molecule is. Analytical methods are typically developed, qualified, and validated in step with the clinical... 

There are several natural milestones during drug development, and although there are differences between companies, both in the number and in the names of the milestones, these differences are quite small. The first milestone is the selection of a compound in the drug discovery phase for development. In the past this decision was exclusively based on the pharmacology (potency, selectivity) of the compound. Since there is now greater awareness that compounds with attractive pharmacological properties may fail later because of poor solubility or extensive metabolism, the physical chemistry, preliminary PK and metabolism characteristics of the... 

At times, a drug that affects more than one target simultaneously may be preferable for specific indications because of desired consequences, such as enhanced potency, wider therapeutic efficacy (e.g., greater spectrum of activity in a heterogeneous condition such as major depression), faster onset of desired activity, or better tolerability. There are four goals of new drug development ... 

As drug development became of greater importance during the first half of the twentieth century, a more quantitative and analytical foundation was needed to assess drug potency per se as well as comparative drug potency. The standardization and quantification of technique and experimental design, and the rigorous application of statistical analysis, have provided pharmacodynamics with a necessary solid base. 

The structure of NPI-0052 offered unique substitutions about the y-lactam-(3-lactone ring system with functional groups that significantly enhanced its potency and potential for drug development, as highlighted in this account. 

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