The influence of lipophilicity in drug discovery and design

Abstract

A current review of the literature reveals a continued reliance on the synthesis of novel structures with increased potency, rather than a focus on maintaining optimal physicochemical properties associated with ADMET throughout drug optimization. Particular attention to the optimum region of lipophilicity, as well as monitoring of lipophilic efficiency indices, may contribute significantly to the overall quality of candidate drugs at different stages of discovery.

Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo

“…The increase in both parameters can be partly attributed to the presence of the lipophilic iodine-bearing benzyl moieties as plasma protein binding interactions are hydrophobic in nature. 21 Despite the increase in lipophilic properties, the log P oct values of compounds 5, 7 and 9…”

Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors

“…Unfortunately, this compound was highly lipophilic (c log D = 4.4) 11 and was not progressed due to the likelihood of ADME liabilities. 12 Our expectation was that the change from a phenyl to a pyridyl ring would, as a result of decreasing lipophilicity, improve drug-like properties, such as solubility and metabolic stability. 13 that the additional nitrogen might improve PAK1 potency by reducing the pK a of the donor NH of the indole, allowing for a stronger hydrogen-bonding interaction with the backbone carbonyl of Asp393 in the ribose pocket.…”

The Block Relevance (BR) analysis to aid medicinal chemists to determine and interpret lipophilicity

“…The importance of lipophilicity in medicinal chemistry is widely known 1 in particular, to improve the efficiency of compounds development by minimizing the attrition rate and shortening the development time; and to satisfy the modern medicinal chemistry demands for physicochemical property determinations (e.g. 20 lipophilicity) required for the early prediction of ADME profile [2][3][4][5][6] .…”