The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists

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Abstract

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

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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