The Discovery of GSK2251052: A First-in-Class Boron ... - Anacor
The Discovery of GSK2251052: A First-in-Class Boron ... - Anacor
The Discovery of GSK2251052: A First-in-Class Boron ... - Anacor
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14<br />
<strong>Class</strong>ical <strong>Boron</strong>ic Acids Have Significant<br />
Limitations<br />
O<br />
H<br />
N<br />
OH<br />
B OH<br />
Most boronic acid enzyme<br />
<strong>in</strong>hibitors conta<strong>in</strong> an aliphatic<br />
carbon-boron bond<br />
Consequences <strong>of</strong> an aliphatic carbon-boron bond<br />
–Chemical reactivity is moderate and can lead to over reactivity<br />
with non-target prote<strong>in</strong>s – poor selectivity & specificity<br />
–Stability problems <strong>of</strong>ten arise via oxidation or proto-debor<strong>in</strong>ation<br />
–Oxidative metabolism can lead to elim<strong>in</strong>ation <strong>of</strong> boron and loss<br />
<strong>of</strong> biological activity<br />
–pKa range <strong>of</strong> 8-9 favors trigonal form <strong>in</strong> aqueous environment<br />
–Can pose synthetic challenges
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