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CHAPTER 1

Physicochemical Properties and Compound Quality

The pharmaceutical industry is facing unsustainable levels of attrition, with 96% or more of candidates failing in development. The observation that marketed oral drugs have restricted physicochemical properties, which are distinctly different from current medicinal chemistry, provides a viable hypothesis to tackle the attrition problem. The history of medicinal chemistry suggests that balancing the lipophilicity (or hydrophobicity) of drug candidates is central to successful outcomes. Thus, while highly lipophilic molecules often have high affinity for the biological target, in general they show increased risk of poor ADMET properties and increased attrition in drug development. While it is possible to discover drugs that lie at the perimeter of oral drug-like space, a portfolio composed of such molecules would suffer predictable high attrition, and would require serendipity for its success. The common practice of primarily optimizing potency in vitro has the potential to introduce unnecessary bias to drug design practice. A solution is to make better use of multi-parameter optimization, where emphasis is placed collectively on the potency and ADMET properties expected to modulate the specific disease.

Publication details


Print publication date
09 Dec 2014
Copyright year
2015
Print ISBN
978-1-84973-625-1
PDF eISBN
978-1-78262-183-6