The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists
Directed screening of a carboxylic acid-containing combinatorial library and subsequent optimization led to the discovery of potent inhibitors of the integrin VLA-4. Optimization of the initial lead led to substituted biphenyl derivatives 37 with low picomolar activities. Pharmacokinetic characterization revealed rapid plasma clearance and poor to moderate oral bioavailability.
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Acknowledgments
The authors are grateful to Zhen Wang, Junying Wang, and Song Zheng for formulation and mass spectral analysis of pharmacokinetic samples and to Marcie Donnelly for dosing of animals for pharmacokinetic evaluation.
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