Bioisosteric Groupings to Improve Target Potency

The authors reported that the phenoxide anion is a key interaction in the receptor-antagonist interaction that may explain the differences in potency between the two compounds. Compound 35 has a pK of 8.6, compared to a pfQ, of 9.1 for the corresponding urea 34. Interestingly, the squaramide series has generally lower clearance and lower volume of distribution, suggesting higher plasma protein binding. 

Often hit compounds from an HTS screen are laden with undesirable functional groups that need to be removed or replaced with suitable bioisosteres. It can be 

Through fragment-based drug discovery, coupled with X-ray and NMR data, researchers at Abbott discovered ABT-737 that had remarkable biological activity, but modest exposure in rat, as judged by the area under the curve (AUC). The compound was also extremely lipophilic and therefore had poor water solubility ( l[ig/ml). Attempts were made to improve the rat oral pharmacokinetics of ABT-737 and to build SAR for the parts of the molecule that could modulate the 

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