Lead optimization application

Lead optimization Application of early ADMET predictive techniques, structure-activity relationships and medicinal chemistry testing of homologs... 

Convex hull formulations of MILPs and MINLPs lead to relaxed problems that have much tighter lower bounds. This leads to the examination of far fewer nodes in the branch and bound tree. See Grossmann and Lee, Comput. Optim. Applic. 26 83 (2003) for more details. 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

Additional applications of this technology for rapid lead discovery and lead optimization have been reported [87, 90-93]. It should also be noted that a variety of chemical transformations, in particular in the area of transition-metal catalyzed reactions, have been performed with this or related equipment (Chapt. 11) [25]. Other monomode microwave reactors using related concepts to introduce high-throughput were recently introduced by CEM Corp. (Discover or Explorer line of products, Fig. 12.7.) [81]. At the time of writing this review no published synthetic applications using this microwave reactor were available. 

J. P. Whitten, Y. E Xie, P. E. Erickson, T. R. Webb, E. B. De Souza, D. E. Grigoriadis, J. R. McCarthy, Rapid Microscale Synthesis, a New Method for Lead Optimization Using Robotics and Solution Phase Chemistry Application to the Synthesis and Optimization of Corticotropin-Releasing Factor Receptor Antagonists , J. Med. Chem. 1996,39, 4354-4357. 

The pharmaceutical industry has pioneered in the application of computer-assisted drug design methods in product research. To a significant degree this is a consequence of the direct use of computational chemistry in enhancing the efficiency of the chemical lead optimization process. 

P., Whipple, D. A., Soloweiij, J. E., Chowd-hary, S., Treasurywala, A. M. (1996) Application of genetic algorithm to combinatorial synthesis a computational approach to lead identification and lead optimization. J Am Chem Sot 118, 1669-1676. 

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