An update on lipophilic efficiency as an important metric in drug design

ABSTRACT

Introduction

Lipophilic efficiency (LipE) and lipophilic metabolic efficiency (LipMetE) are valuable tools that can be utilized as part of a multiparameter optimization process to advance a hit to a clinical quality compound.

Areas covered

This review covers recent, effective use cases of LipE and LipMetE that have been published in the literature over the past 5 years. These use cases resulted in the delivery of high-quality molecules that were brought forward to in vivo work and/or to clinical studies. The authors discuss best-practices for using LipE and LipMetE analysis, combined with lipophilicity-focused compound design strategies, to increase the speed and effectiveness of the hit to clinical quality compound optimization process.

Expert opinion

It has become well established that increasing LipE and LipMetE within a series of analogs facilitates the improvement of broad selectivity, clearance, solubility, and permeability and, through this optimization, also facilitates the achievement of desired pharmacokinetic properties, efficacy, and tolerability. Within this article, we discuss lipophilic efficiency-focused optimization as a tool to yield high-quality potential clinical candidates. It is suggested that LipE/LipMetE-focused optimization can facilitate and accelerate the drug-discovery process.

KEYWORDS:

• Multiparameter optimization
• drug discovery
• lipophilicity
• structure based drug design (SBDD)

Article highlights

• The benefits of using a LipE analysis can be maximized if LogD is measured for all synthesized compounds with prospective use of a computational LogD prediction protocol for proposed new analogs if it shows good correlation with measured data.

• Additionally, utilization of a potency assay for LipE analysis that is most likely to predict in vivo efficacy, ideally a relevant cell-based assay, will increase the effectiveness of this drug design paradigm. Similarly, the in vitro clearance assay selected for LipMetE analysis should be that most relevant to in vivo clearance. The effects of binding in both potency and clearance assays should be accounted for.

• Published case studies that effectively used LipE analysis, discussed herein, monitored the relationship between LogD and ADME properties, particularly clearance, through the use of LipMetE analysis. In these examples, structure-based drug design together with deliberate modulation of lipophilicity in the context of co-crystal structures and ADME goals was shown to be a powerful approach.

• Far more knowledge for design can be gleaned from scrutiny of 2D LipE plots as opposed to data tables. In the literature, presentation of data in tables can be useful, but when multiple data types and compounds are included, it can be challenging to identify key learnings needed to guide design of new compounds using this format.

• Multiple use cases for the effective use of the LipE/lipophilicity/LipMetE paradigm, coming from small and large companies as well as academia, are discussed and referenced in this work.

Declaration of interest

All authors are presently or former employees of Pfizer Inc. who are shareholders. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Notes

1. For the purpose of this review, we define an optimized lead to be a compound considered as one of the highest quality of the series, although not a clinical candidate.

Additional information

Funding

This paper was not funded.