Michael P. Balogh
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As I was deciding which talks from the 2006 Conference on Small Molecule Science to summarize for this column, I noted that,
purely by chance, the opening and the closing talks presented a logical symmetry. The closing talk given by Charles McEwen,
a highly regarded DuPont scientist, considers readily available adaptations of mass spectrometry technology he has developed
to solve a diversity of problems and is planned for a succeeding column. This month's installment of "MS — The Practical Art"
reprises Chris Lipinski's talk, from the opening session chaired by Michele Kelly of Pfizer, which examines the analytical
road ahead in drug discovery and the quest to expand the chemistry landscape and its inherent analytical demands.
Retired from Pfizer (Pfizer Global R&D, Groton, Connecticut), Lipinski is now a science advisor for Melior Discovery (Exton,
Pennsylvania). Many will recognize his name, as they will have heard him speak of the highly regarded "Rule of Five" that
characterizes the majority of successful drugs in the market today.
Chemistry structures for all drugs are constrained by fundamental principles. However, Lipinski develops an issue that underpins
the discovery process: the tendency for medicinal chemists and biologists to disagree.
Biologists have targets they love — wonderful targets from a biological perspective like protein–protein interactions. But
the hit rate in screening for many of those targets is absolutely horrible, and that frustrates the biologists. In some ways,
[they seem to] take out their frustration on the chemists, characterizing them as an uncooperative and stubborn lot, too fixated
on rules, principles, and what they believe it takes to make a good drug. Now if we could expand the properties base of the compound, perhaps we would succeed against these very difficult and important
targets. But instead, we have a battle between biologists and the chemists, and the chemists say, 'No, given what we currently
know, we can't succeed against that target.' In some organizations, depending on cultural conditions, the biologists prevail.
The properties of a real, orally active, drug-like compound, resonates with medicinal chemists.
Figure 1
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About Figure 1, Lipinski says — perhaps surprising to some of us — that regarding drug-like properties, the leads usually
are inferior in all three areas. For example, a chemist might start out with a 1 μM lead compound and try to optimize its
potency. Of course, he or she would like to improve the compound's solubility and permeability as well. If the chemist focuses
on potency alone, optimizing the compound from 1 μm to, say, 10 nM — it now falls somewhere below the surface on the graph.
So the chemist makes a wonderful ligand — very potent but not useful if not orally active. If the business plan under which
the chemist was working were to develop an orally active compound, that compound would fail to make money, and just as significantly,
it also would do nothing to help patients. Unfortunately, this scenario is extremely common. Generally, when you improve in
vitro potency only, you not only fail to improve permeability and solubility, but you often worsen those properties — that
is, what would make it a good orally active drug candidate.
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