Pullan Consulting
Biotech Business Development Consulting
lpullan@msn.com 805-558-0361
Issue #18
Pullan's Pieces
Commentary on Science & Business of Drug Development
For Business Development & Others
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Increased lipophilicity in recently synthesized new drug candidates may mean greater attrition in development
The Lipinsky rule of 5 describing the criteria for small synthetic molecules to be drug-like has now been around for a decade. The rule of five, which was derived from a database of clinical candidates reaching Phase II trials or further, states that poor absorption or permeability are more likely when cLogP (the calculated octanol–water partition coefficient, a measure of lipophilicity) is >5; molecular mass is >500 daltons; the number of hydrogen bond donors (OH plus NH count) is >5; and the number of hydrogen bond acceptors (O plus N atoms) is >10.
Paul Leeson and Brian Springthorpe (Nature Reviews Drug Discovery 6: 881-890; http://www.nature.com/nrd/journal/v6/n11/abs/nrd2445.html) analyzed molecules being synthesized now and compare their characteristics to historical drugs. They find a dramatic increase in lipophilicity in the newly synthesized drug candidates. They believe this increase in lipophilicity increases the risks of a lack of selectivity for target interactions and for attrition in the drug development process. (My speculation is that since many high-affinity target interactions are specific ionic pairs, that increasing lipophilicity increases the contribution of less specific hydrophobic regional target interactions shared by multiple targets). The change in what kinds of molecules are synthesized and patented over time may reflect the increasing challenges of newer drug targets, but the authors also find that different pharmaceutical companies have different tolerances for moving away from the tight rule of 5 characteristics. Leeson and Springthorne suggest tightening the lipophilicity criteria for molecules to be made could change the attrition by 5% and double the output of small molecule new medicines!
A sticky message- simple, concrete and surprising to be remembered and change thinking
JFK’s “Put an American on the moon in a decade” was a sticky message, one that people remember and that changed thinking (Chip Heath in McKinsey’s Quarterly Nov 2007, http://www.mckinseyquarterly.com/Strategy/Strategic_Thinking/Crafting_a_message_that_sticks_An_interview_with_Chip_Heath_2062_abstract ). You make a message sticky by keeping it simple, and making it concrete and surprising. Simplicity is identifying the core elements and highlighting them. To be concrete, substitute stories for abstractions. And highlight the unexpected for a touch of surprise.
I’ll try to remember Chip’s guidance in my next partnering communication. I think we scientists often suffer from a love of details. Keeping it simple doesn’t mean leaving the detail out, but can mean that each slide headline is a message, and that same takeaway is listed on introduction and conclusion slides. Simplicity can mean reducing the field-specific jargon and substituting action words. For partnering presentations, a place to think about concreteness may be the potential impact of your therapy. The most powerful impact is a story about changing a person’s life. And successful drugs do change lives.
Correction: 4SAC’s Phase II dihydroorotate dehydrogenase inhibitor for RA is unpartnered and available for licensing.
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Thank you for a great year of consulting in 2007; I look forward to more biotech business development in 2008.
I wish you all a Happy Holiday and a Great 2008!
Linda
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Pullan Consulting
Linda M. Pullan, Ph.D.
Biotech Business Development
lpullan@msn.com
805-558-0361
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