Drug optimizing properties

When assayed in HEK293 cells transfected with the cloned human, rat and guinea pig TRPVl, (23a) showed similar potencies. Not unexpeetedly, (23a) showed poor metabolic stability and a structure-activity study to optimize potency and drug-like properties was initiated. Modification on the left-handed A -aryl section showed that ... 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

Volume IV Optimizing the Drug-Like Properties of Leads in Drug Discovery... 

Further tests are carried out to evaluate the potency and specificity of the isolated lead compounds. This is usually followed by modifications of the compounds to improve properties through synthesis of variations to the compounds via chemical processes in the laboratory and frequently with modifications to the functional groups. The optimized lead compounds go through many iterative processes to keep improving and optimizing the drug interaction properties to achieve improved potency and efficacy. 

The SA protocol has also been successfully applied to optimize drug-like properties or ADME parameters while maximizing diversity and/or predicted... 

Classical structure modifications have been the mainstay of drug optimization since the earliest days. As emphasized earlier at several points, structural modifications expressed in organic chemical terms are really only symbols for modification of the physicochemical properties of various structures. Nevertheless, the medicinal chemist usually thinks in terms of structure, since that is the language of organic synthesis. It is therefore appropriate to deal with such an approach, provided one keeps in mind that it is somewhat obsolete because it is twice removed from the arena of drug-receptor interactions. 

In some instances, researchers are able to develop separate Hansch equations for both activity and toxicity of a drug. Differing parameters between the activity and toxicity QSAR equations allow researchers to optimize properties that boost desired activity and minimize toxicity. The following two QSAR equations give the activity (12.d) and toxicity (12.e) for a series of nitrogen mustard antitumor compounds (see Chapter 6). Based on these equations, is it likely that a nontoxic nitrogen mustard will be developed Explain. 

The process of discovery of a new clinical candidate for a novel drug consists of several steps, which have to be iteratively repeated in order to obtain the structure of high potency with drug-like properties. The first and crucial for the whole project step is a choice of the proper molecular target of the drug — an enzyme or a molecular receptor. Then lead generation process and its subsequent optimization results in some candidates for clinical trials. 

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