Lead optimization overview

Overview of Hit to Lead The Medicinal Chemist s Role from HTS Retest to Lead Optimization Hand Off. 1... 

Pharmacokinetics and toxicity have been identified as important causes of costly late-stage failures in drug development. Hence, physicochemical as well as ADMET properties need to be fine-tuned even in the lead optimization phase. Recently developed in silica approaches will further increase model predictivity in this area to improve compound design and to focus on the most promising compounds only. A recent overview on ADME in silica models is given in Ref [128]. 

This section will provide an overview on ADME models from our group to illustrate our approach for building predictive models on structurally diverse training sets. Datasets for intestinal human absorption and human serum albumin binding are discussed, while models for other relevant ADME properties have also been obtained. Those models, however, do not stand alone but are used in combination with those models tailored for affinity and selectivity in the frame of multidimensional lead optimization. 

This contribution will give a general overview of current molecular modeling approaches for lead identification and lead optimization based on molecular structure information. 

This chapter provides an overview of the history of bioisosterism from its begiim-ing in the early twentieth century to the present day. We also provide an overview of the importance of judicious bioisosteric replacement in lead optimization to assist in the path toward a viable clinical candidate and, ultimately, a drug. 

Lipinski CA (2010) Overview of hit to lead the medicinal chemist s role firom HTS retest to lead optimization hand off. In Hayward MM (ed) Lead-seeking approaches topics in medicinal chemistry, 5th edn. Springer, Berlin, pp 125-140... 

The previous sections have described methods to obtain 2-pyridone scaffolds. Both in the construction of new materials and especially in drug design and development, there is a desire to be able to derivatize and optimize the lead structures. In the following sections, some recent developments using MAOS to effectively substitute and derivatize 2-pyridone heterocycles are described. The reaction types described range from electrophilic-, and nucleophilic reactions to transition metal-catalyzed transformations (Fig. 7). To get an overview of how these systems behave, their characteristics imder conventional heating is first described in brevity. 

Nicewonger R, Baldino C, Evans M (2003) The accelerated development of an optimized synthesis of 1,2,4-oxadiazoles. Tetrahedron Lett 44 9337-9341 Ondruschka B, Nuchter M, Bonrath W (2004) Microwave assisted synthesis— a critical technology overview. Green Chem 6 128-141 Regan J, Breitfelder S Cirillo P (2002) Pyrazole urea-based inhibitors of p38 MAP kinase from lead compound to clinical candidate. J Med Chem 45 2994-3008... 

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