Lead Optimization and Candidate Selection

Robust SAR IP space Selectivity Physicochemistry In vitro ADME PK and brain penetration Cardiac safety In vitro toxicity 

CYP2D6, 3A4 10uM Cl (rat miorosomes) 1 pL/min/mg protein Papps (Caco-2) 87 nm/sec hERG ICso 30 pM 

The same strategy was applied to lactams with the hope to also increase permeability and brain penetration. Data obtained (not shown) were encouraging but the introduction of the cyclobutoxy linker in that series unfortunately significantly increased human and rodent microsomal clearances resulting in worsened PK profiles (higher clearances, higher volumes) and less consistent results in behavioral models. Efforts were, therefore, focused on cyclobutoxy fused thiazole series for which the overall properties profile seemed much more balanced. 

We nevertheless thought that the price to pay, in terms of molecular weight, lipophihcity (hence hpophihc ligand efficiency, LLE), and scaffold complexity, to eventually get an optimized profile was important 

We decided to take a step back and revisit some previous series with the objective to simplify the right-hand side of the molecule (fused thiazoles) and capitalize on the benefits offered by the cyclobutoxy spacer. 

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Figure 2. DMPK screening paradigm as part of the lead optimization and candidate selection process-application to HCV compound selection.

After optimization, scientists test the lead compounds in more sophisticated models including pharmacokinetics, pharmacodynamics, and toxicity. The optimal molecule selected from these assessments is then declared a new dmg candidate and moves on to the next phase (development). If a program is successful, it may take a total of 3-6 years from target selection and validation through lead generation, lead optimization, and preclinical evaluation in animals to candidate selection for a potential new medicine. 

Balani SK, Miwa GT, Gan LS, et al. Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Curr Top Med Chem. 2005, 5(11) 1033-1038. 

As the drug discovery process proceeds from early lead discovery through lead optimization and toward candidate selection, the level of purity required of each compound increases. Late-stage compounds may be tested in multiple assays, many of which may involve animal models and may be labor-intensive. Even the best solid phase combinatorial synthesis methods cannot assure that... 

In this chapter, we will describe the history and process of lead discovery from initial target identification and disease validation through the lead identification process itself, culminating in lead optimization and pre-clin-ical candidate selection. The full range of technologies and approaches that have been brought to bear on this complex activity will also be highlighted. 

Chaubal, M. Application of drug delivery technologies in lead candidate selection and optimization. Drug Discov. Today 2004, 9, 603-609. 

A model for predicting oral bioavailability is an important tool, both in the early phases of drug discovery to select the most promising leads for further optimization, and in the later stages to select candidates for clinical development. The... 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

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