Lipophilic efficiency

Fig. 10.8. Cellular activity and hepatocyte stability of the 37 purified library compounds, (a) cLipE vs. human np-HSD1 EC50 (hHEKEC50). Chart enables rapid identification of the active and lipophilic efficient compounds (in lower right corner), e.g., PF-03440171 with cLipE = 8.7 and EC50 = 0.03 nM. (b) Fluman hepatocyte intrinsic apparent clearance (GLJiFlepCI) vs. hHEKEC50. Chart enables rapid identification of active and metabolically stable compounds, such as PF-03440142 with GLJiFlepCI = 5 pl/min/million and EC50 = 67 nM.

V. A., Correia, A. M., Owen, D. R., Thompson, L. R, Tran, I., Tutt, M. F., Young, T. (2009) Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols a lipophilic efficiency (LipE) analysis. Bioorg Med Chem Lett 19(15), 4406-4409. 

A recently reported tool for hit evaluation and prioritization is ligand lipophilicity efficiency (LLE).21 LLE is calculated as the difference between the negative logarithm of a hit s binding affinity, such as —log /C50 or —log KD, and the logarithm of a hit s partition coefficient, such as log P or clog P (Equation 10.2). 

Edwards, M. P., Price, D. A. Role of Physiochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks. Annu. Rep. Med. Chem. 2010, 45, 381-391. 

Mortenson PN, Murray CW (2009) Ligand lipophilicity efficiency - assessing lipophilicity of fragments and early hits. Presented at RSC Fragments 2009, Astra Zeneca Alderley Park, UK, 4—5 March 2009, Poster 9... 

Lewis, M.L. and Cucurull-Sanchez, L. (2009) Structural pairwise comparisons of HLM stability of phenyl derivatives introduction of the Pfizer metabolism index (PMI) and metabolism-lipophilicity efficiency (MLE). Journal of Computer-Aided Molecular Design, 23 (2), 97-103. 

Lewis ML, Cucurull-Sanchez L. Structural pairwise comparisons of HLM stabdity of phenyl derivatives Introduction of the Pfizer metabohsm index (PMI) and metabohsm-lipophilicity efficiency (MLE). J Comput Aided Mol Des 2009 23 97-103. 

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. 

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