Lipophilicity Efficiency

The first publication describing an LLE-focused optimization was a rapid assessment of a novel series of selective CB2 agonists using parallel 

An approach that integrated structure-based drug design with physicochemical properties-based approaches to optimizing drug candidate 

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 

Optimization of the large (MW = 512), lipophilic (clogP = 7.6), and very potent (Kj = 0.22 nM) Vascular Endothelial Growth Factor Receptor Tyrosine Kinase (VEGFR TK) inhibitor 8 (LLE = 2.1) to produce the development candidate axitinib (9) was recently reported [17]. 

Finally, a lead optimization program that utilized a strategy to maximize LipE in a series of aminopyrrolidines produced the broadly selective, potent adenosine-5 -triphosphate (ATP)-competitive Akt inhibitor 11 (Akt IC50 1 nM, clogP = 2.4, LipE = 7.2) which was nominated for clinical development [18]. 

---

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. 

---