Drug discovery and development is a multiobjective problem.   Unfortunately, it is easy to focus exclusively on in vitro activity against the therapeutic target and not consider absorption, distribution, metabolism, excretion, and toxicity (ADMET) until late in a development program.  The predictable result is late-stage failures.Lipinski et al. [1] formulated the �Rule of 5� to identify compounds having a molecular weight (MW), logP value, and hydrogen bond donor and acceptor count higher than most orally available drugs.  We have used a newer, more refined reference set of drugs from the World Drug Index to develop an extended set of rules that go beyond potential absorption problems to include many other kinds of predictable ADMET liabilities. Our ADMET Risk� includes 24 composite rules that consider everything from size to lipophilicity to likely metabolism to mutagenic potential.  The number of rule violations is complemented by a list of mnemonics (the ADMET Code�) to indicate which, if any, rules were violated by a particular structure. We also replaced the single value thresholds typical of filters like the Rule of 5 with ranges [2] that start at levels satisfied by 85% of the reference set and ramp up to a full penalty value at levels satisfied by just above 90%, so a compound with MW 495 does not go unpenalized while one with MW 505 gets a full demerit.About 90% of the reference set has an ADMET Risk score below 6.5.  We will illustrate how the scores and mnemonic codes can be used together with the series identification, combinatorial, and graphical analysis tools in MedChem Studio� to prioritize drug development leads in a truly multidimensional manner. _________________________________________________________________________1. CA Lipinski et al., Adv Drug Delivery Rev 2001 , 46:3�26.2. J Petit et al., Bioorg Med Chem 2012 , 20:5343�5351.

Looking beyond a few hard cutoffs in assessing ADMET Risk<sup>TM</sup>

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Looking beyond a few hard cutoffs in assessing ADMET RiskTM

Looking beyond a few hard cutoffs in assessing ADMET Risk^TM