Hit-to-lead optimization

Two recent communications described the hit-to-lead optimization which ensued from the original screening hit 10 [82,83]. From this research, four new... 

Kariv, I., Rourick, R.A., Kassel, D.B., and Chung, T.D.Y. Improvement of hit-to-lead optimization by integration of in vitro HTS experimental models for early determination of pharmacokinetic properties. Comb. Chem. High Throughput Screen. 2002, 5, 459-472. 

Reactive, unstable compounds, as well as covalent binders, can be removed from screening collections by substructure searches [21, 22]. At Roche, a global team of experienced medicinal chemists has defined more than 100 functionalities which are reviewed at regular intervals. This list has been augmented by unwanted features (e.g., polyacids, alkyl aldehydes, polyhalogenated phenols, etc.) which are chemically unattractive starting points for a hit-to-lead optimization, because they often result in non-optimizable SAR patterns. These chemotypes have been coded into Markush-type substructures for automated detection and removal of unwanted compounds. However, we need to stress that these filters are fully customizable, and removed chemotypes can be restored if required. 

In another recent effort, Poulain and co-workers illustrate the improvements in efficiency that focused libraries can bring to early lead optimization. The authors describe the hit-to-lead optimization of J, opiate ligands, starting with a micromolar hit from HTS. Using a pharmacophore-based approach, several focused libraries were designed and synthesized, as illustrated in Scheme 8. Combining the results of these libraries suggested a series of chimeric compounds, which exhibited subnanomolar activity and improved physico-chemical properties. 

Using the TNAP inhibitors developed in our lab as a case study what follows is a more detailed account of how these properties were assessed and utilized in a hit-to-lead optimization procedure. 

The combined VS hit list is summarized in Fig. 4. In addition to the sets described in Subheading 2.2, the virtual hit lists includes 650 compounds from previous lead-finding activities on MDM2 (hit finding and hit-to-lead optimization assays). After elimination of duplicates, the hit list includes 46,511 unique compounds which were available at the Novartis compound archive via HTCP. 

Enyedy I.J. and Egan, W.J. (2008) Can we use docking and scoring for hit-to-lead optimization Journal of Computer-Aided Molecular Design, 22, 161—168. 

Hit-to-Lead Optimization Using Iterative and Parallel-Focused... 

All these measures together have greatly increased the proportion of true hits so that, finally, the chemistry capacities are concentrated on fewer but well-characterized hit classes with a clearly increased likeliness of a successful hit-to-lead optimization (Fig. 32.5). 

Select appropriate metrics for multidimensional optimization use ligand efficiency and lipophilic efficiency metrics in hit-to-lead optimization and change to more complex metrics emphasizing dosage to support lead optimization. 

Prioritization of chemical series then follows taking into consideration parameters such as (i) dynamic, reproducible SAR , (ii) structural novelty, and (iii) synthetic feasibility and amenability toward hit-to-lead optimization. Three possible scenarios emerge depending on the primary objective of the campaign ... 

I) Target discovery goal Completion of all the screens, triaging, and prioritization yield chemical series with attractive phenotype that have little to no possibility to be adopted for medicinal chemistry hit-to-lead optimization for various reasons (nonlead-like properties, IP, etc.). Still, the discovery of a novel target in the disease biology context grants follow-up toward appropriate chemical probes for mechanism of action elucidation. 

Tajima, N Yamashita, T Vitt, D., and Noda, H. (2011) Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorganic and Medicinal Chemistry Letters, 21, 5417-5422. 

Li B, Cociorva OM, Nomanbhoy T, Weissig H, Li Q, Nakamura K, Liyanage M, Zhang MC, Shih AY, Aban A, Hu Y, Cajica J, Pham L, Kozarich JW, Shreder KR (2013a) Hit-to-lead optimization and kinase selectivity of imidazo[l,2-a]quinoxalin-4-amine derived JNKl inhibitors. Bioorg Med Chem Lett 23(18) 5217-5222. doi 10.1016/j.bmcl.2013.06.087... 

Sypchenko VV, Potikha LM, Kovtunenko VA, Baumer VN, Shishkin OV (2012) Preparation of isoindolo[2,l-a]quinoxalines based on JV-(2-aminophenyl)isoindole derivatives. Chem Heterocyclic Compd 48(7) 1033-1042. doi 10.1007/sl0593-012-1096-x Szabo G, Kiss R, Payer-Lengyel D, Vukics K, Szikra J, Baki A, Molnar L, Fischer J, Keseru GM (2009) Hit-to-lead optimization of pyrrolo[l,2-a]quinoxalines as novel cannabinoid type 1 receptor antagonists. Bioorg Med Chem Lett 19(13) 3471-3475. doi 10.1016/j.bmcl.2009.05. 010... 

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