Drug development optimization

To extract the conformational properties of the molecule that is being studied, the conformational ensemble that was sampled and optimized must be analyzed. The analysis may focus on global properties, attempting to characterize features such as overall flexibility or to identify common trends in the conformation set. Alternatively, it may be used to identify a smaller subset of characteristic low energy conformations, which may be used to direct future drug development efforts. It should be stressed that the different conformational analysis tools can be applied to any collection of molecular conformations. These... 

Since drug development has turned into a systematic and rational task of optimizing molecules and their interactions with proteins, cells, and organisms, combinatorial chemistry has become a significant part of this endeavor. Combinatorial methods are mainly employed in the initial (preclinical) stages of drug development. 

Schjpdt-Eriksen J, Clausen J. Optimization and simulation in drug development—review and analysis http //www.imm.dtu.dk/pubdb/views/edoc download.php/2834/ps/imm2834.ps... 

Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

E. Lipka and G. L. Amidon, Setting bioequivalence requirements for drug development based on preclinical data optimizing oral drug delivery systems, J. Controlled Release, 62, 41 (1999). 

Tukker, G., Houston, J. B., Huang, S.-M., Optimizing drug development strategies to assess drug metabolism/ transporter interaction potential — toward a consensus, Clin. Pharmacol. Ther. 2001, 70, 103-114. 

Lesko, L.J., Rowland, M., Peck, C.C., and Blaschke, T.F. (2000). Optimizing the science of drug development opportunities for better candidate selection and accelerated evaluation in humans, Pharmaceutical Research 17 1335-1344. 

Drug development is a long and cost-intensive business. Only after years of lead identification, chemical optimization, in vitro and animal testing can the first clinical trials be conducted. Unfortunately, many projects still fail in this late stage of development after a considerable amount of money has been spent. According to estimates, preapproval costs for a new drug exceed US 800 million [1]. 

Irreversible CYP inhibition, especially when considered as a cause of chemically reactive metabolites, raises a number of issues that should be considered early in the drug discovery process. Careful evaluation of the structural features of the lead series as well as screening for MBIs early in the drug development process should guide series selection and optimization with the goal of avoiding the introduction of potentially risky moieties into new chemical entities. 

Examples of PAT applications to drug development are a crystallization process optimization from laboratory to industrial scale [72] optimization of manufacturing steps in pharmaceuticals [70]... 

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