Combinatorial Chemistry and High-throughput Screens

Once the initial diversity fetish had run its course and management realized that it was inefficient to attempt to span the entirety of chemical space in search of drugs, more rational approaches based on chemoinformatics were developed to design combinatorial libraries and select candidates for screening on the basis of properties that have proven to be associated with successful therapeutics in the past. 

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A Stille coupling of a bromopyridine on solid support was described by Snieckus group [101]. Merrifield resin 119 was esterified with 3-bromopyridine-5-carboxylic acid to afford ester 120. The Stille coupling of ester 120 on a solid support led to the expected hetero phenylpyridine 121, which was then cleaved via basic hydrolysis to produce 122. Snieckus work has the potential for application to combinatorial chemistry and high throughput screening. 

The development of combinatorial chemistry and high throughput screening programmes has stimulated efforts to find experimental and computational models to estimate and predict drug absorption, distribution, metabolism and elimination based on drug physicochemical properties. 

In the last 10 years drug discovery has changed rapidly. Combinatorial chemistry and high-throughput screening have been introduced widely and now form the core of the Discovery organizations of major pharmaceutical and many small biotech companies. However, the hurdles between a hit, a lead, a clinical candidate, and a successful drug can be enormous. 

Combinatorial Chemistry and High-Throughput Screening (HTS). The input for new drugs in development is determined by the number of new molecules made available as a whole— libraries —on one hand and targets ... 

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