Target compounds failures

All experiments to completely decarboxylate this dicarboxylic acid seemed to have failed then, and only traces of the target compound could be isolated, not manageable preparatively. Dallacker and Mues were also not able to decarboxylate 3,4-methylenedioxy-thiophene-2,5-dicarboxylic acid (only 3,4-methylenedioxy-thiophene-2-carboxylic add had been prepared via stepwise esterhydrolysis/decarboxylation). The reason of these failures is not completely dear, but it was good luck for the Bayer researchers. When Ahonen... 

The substrate specificity of ACE is low. ACE cleaves a variety of pairs of amino acids from the carboxy-terminal part of several peptide substrates. The conversion of ANGI to ANGII and the degradation of bradykinin to inactive fragments are considered the most important functions of ACE. Both peptides have profound impact on the cardiovascular system and beyond. ACE is thus an important target for ACE inhibitors. These compounds are frequently and efficiently used in the treatment of hypertension and cardiac failure. 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

An analysis of more than 130 preclinical candidates that had attrited during further development showed the failure of the chemotype approach (i.e. that a compound of the same/similar chemotype will have similar risks of attrition and that a structurally diverse chemotype will offer the best approach to minimize attrition risk) and 2D structure-based methods to be able to effectively differentiate compounds [29]. Thus, the risk of failing or succeeding in development is not related to being of the same chemotype , and differentiation by this method may not be the most effective way dangers are both that a valuable series/chemotype could be discarded because of one bad result and that a structurally different compound may actually have similar off-target effects (e.g. due to the decoration versus the scaffold). 

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