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
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]
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.