2. Academic Validation
  3. The discovery of sulfonylated dipeptides as potent VLA-4 antagonists

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists

  • Bioorg Med Chem Lett. 2001 Oct 22;11(20):2709-13. doi: 10.1016/s0960-894x(01)00544-3.
W K Hagmann 1,  P L Durette,  T Lanza,  N J Kevin,  S E de Laszlo,  I E Kopka,  D Young,  P A Magriotis,  B Li,  L S Lin,  G Yang,  T Kamenecka,  L L Chang,  J Wilson,  M MacCoss,  S G Mills,  G Van Riper,  E McCauley,  L A Egger,  U Kidambi,  K Lyons,  S Vincent,  R Stearns,  A Colletti,  J Teffera,  S Tong,  J Fenyk-Melody,  K Owens,  D Levorse,  P Kim,  J A Schmidt,  R A Mumford
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. william_hagmann@merck.com
PMID: 11591507 DOI: 10.1016/s0960-894x(01)00544-3
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.

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