C32-O-imidazol-2-yl-methyl ether derivatives of the immunosuppressant ascomycin with improved therapeutic potential

  • Bioorg Med Chem Lett. 1998 Aug 18;8(16):2253-8. doi: 10.1016/s0960-894x(98)00397-7.
M T Goulet  1 ,  S R McAlpine ,  M J Staruch ,  S Koprak ,  F J Dumont ,  J G Cryan ,  G J Wiederrecht ,  R Rosa ,  M B Wilusz ,  L B Peterson ,  M J Wyvratt ,  W H Parsons
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
PMID: 9873523 DOI: 10.1016/s0960-894x(98)00397-7
Abstract

A series of C32-O-aralkyl ether derivatives of the FK-506 related Macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.