Strategies to optimize drug half-life in lead candidate identification

ABSTRACT

Introduction: The PK optimization of drug candidates is one of the most resource-intensive tasks in pharmaceutical research and development. With the increasing availability of in silico, in vitro and mechanistic in vivo ADME models, drug discovery scientists have progressively learned to recognize common SAR patterns and engineer data-driven strategies to accelerate the resolution of ADME issues in lead optimization. Many of these strategies gravitate toward the concept of drug-likeness, which defines a number of optimal holistic physicochemical parameters (such as lipophilicity) that idealized oral drugs possess.

Areas covered: Herein, the authors discuss the interplay of lipophilicity with in vitro and in vivo ADME data in order to refine existing thought around drug half-life optimization. Strategies to prolong the half-life of oral drugs via formulation are beyond the scope of this review.

Expert opinion: Optimizing active properties such as potency, selectivity, and intrinsic metabolic clearance is an unambiguously beneficial strategy for small molecules within or beyond the Lipinski rule of five chemical space. The data that we present in this work suggests that emphasis should be primarily placed on optimizing active properties such as potency, selectivity, and metabolic stability.

KEYWORDS:

• ADME
• dose projection
• half-life
• lipophilicity
• medicinal chemistry
• metabolite identification

Article highlights

• Drug half-life is determined by the ratio between V_ss and CL, independent primary PK parameters that tend to be highly correlated.

• Optimizing CL without decreasing V_ss (or vice-versa) is rewarding from dose optimization standpoint.

• Decreasing lipophilicity is usually an efficient strategy to optimize exposure, not half-life.

• A decrease in promiscuity resulting from lower lipophilicity could deteriorate the drug safety profile if dose and C_max are negatively affected by a decrease in T_1/2.

• Addressing the major metabolic soft-spot with topological modification is in most cases a rewarding strategy in terms of dose optimization.

• Optimizing active properties such as potency, selectivity and intrinsic metabolic CL is an unambiguously beneficial strategy for small molecules within or beyond the Lipinski rule of five chemical space.

This box summarizes key points contained in the article.

Declaration of interest

CE Hop is a Senior Director and M Wright a Director for Genentech Inc. G Broccatelli is also an employee of Genentech Inc. 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.

Additional information

Funding

All authors are employees of and are supported by Genentech Inc.