Preclinical candidates

At least four clinical candidates including GSK-256073 [112], MK-0354 [102], MK-1903 [113], and INCB-19062 [91], and one preclinical candidate MK-6892 [77] have been reported. Neither the structure of GSK-256073, nor the clinical data, has been reported. In Phase II clinical trials, neither GPR109A partial agonist MK-0354, nor the full agonist MK-1903 showed substantial lipoprotein effects, and both candidates were discontinued. INCB-19062 is targeted to a type II diabetes indication based upon the related role of FFA to insulin sensitization in type II diabetes, and the robust FFA lowering effect observed in a Phase I clinical trial devoid of FFA rebound. 

CS, preclinical candidate selection I I II I, first time in human PI, phase 1 P2, phase 2 POC, proof of concept. 

Herbst et al.2 described automated high-throughput ADME/Tox profiling for optimization of preclinical candidates, a Profiling Toolkit enables researchers to request profiles, track progress, receive notification when the requests have been filled, and view data. Automated systems and bar coding improve efficiency, help track compound and plate locations, and create audits trail of the profiling process. 

Herbst, J.J. and Dickinson, K. 2005. Automated high-throughput ADME/Tox profiling for optimization of preclinical candidate success. Am. Pharm. Rev. 8 96. 

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). 

Table 7.2 Clinical and preclinical candidates derived from fragments...

Maas, J., W. Kamm, and G. Hauck (2007). An integrated early formulation strategy-From hit evaluation to preclinical candidate pro ling.ur. J. Pharm. Biopharm., 66 1-10. 

Fragments should be composed of drug-like chemical matter because substantial parts of a fragment hit will end up in the final lead candidate for in vivo assays. Therefore, we selected our NMR screening library from commercially available compound repositories that have a proven track record in lead discovery (e.g. by many years of use in HTS) and also as they include structures and substructures that occur in known marketed drugs, as well as in clinical and preclinical candidates. This ensures that the fragment library is built on several decades of experience in drug discovery. 

Mass, J., Kamm, W. and Hauck, G. (2007) An integrated early formulation strategy -from hit evaluation to preclinical candidate profiling. European Journal of Pharmaceutics and Biopharmaceutics, 66, 1-10. 

The resulting optimized lead (preclinical candidate), if it displays no toxicity in cell and animal models, becomes a clinical candidate. If this stands the tests of efficacy and safety in humans and overcomes marketing hurdles, a new drug entity will enter the treasure trove of pharmacy. The Box 2.1 will help to appreciate that activity is a necessary but not sufQcient quahty of medicines. There is, of course, no ideal drug in real world, but one has to find a relative optimum. 

The implicit objective of the chapter is to warn medicinal chemists against the danger of over-simplihcation. For too many drug discoverers, biotransformation begins and ends with CYP-catalyzed oxidations. As a result of this narrow view, little is done computationally and experimentally before the development phases to obtain a comprehensive view of the biotransformation of lead and preclinical candidates. One can only wonder about the proportion of metabolism-related side-effects that could have been avoided during clinical phases had medicinal chemists been more attentive to potential toxihcation reactions and drug-drug interactions caused by non-CYP reactions. 

SARMs A Promising Class of Clinical and Preclinical Candidates 287... 

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