The Record—File 453 (Cont.)

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	Synthesis     

	Alkylation of rapamycin (I) with 
2-(tert-butyldimethylsilyloxy)ethyl triflate (II) by means 
of 2,6-lutidine in hot toluene gives the silylated target 
compound (III), which is deprotected by means of 1N HCl in 
methanol (1). Scheme 1.

     Introduction

     The macrolide rapamycin (now designated sirolimus) (I), 
a secondary metabolite of Streptomyces hygroscopicus 
originally described as an antifungal agent in the mid 
1970s, was subsequently reported in 1989 to effectively 
suppress the rejection of transplanted allogenic solid 
organs in experimental animals (2,3). In contrast to 
cyclosporine and FK-506, which act early after T cell 
activation by blocking transcriptional activation of 
early T cell-specific genes thereby inhibiting synthesis 
of T cell growth factors () which drive proliferation, 
rapamycin also suppresses proliferation at the late G1 
stage of the cell cycle. Thus, the proliferative signal 
provided by T cell growth factors is blocked and cells 
are unable to enter the S phase (4,5). Furthermore, 
inhibition by rapamycin is not limited to IL-2-induced 
T cell proliferation since both hematopoietic and 
nonhematopoietic cell proliferation (e.g., mast cells, 
fibroblasts and vascular smooth muscle cells (VSMC)) 
has been successfully blocked by this agent (6-9).
      Rapamycin has been considered a potential 
candidate to prevent late graft loss resulting from 
graft vessel disease since the agent is capable of 
inhibiting proliferation of VSMC, thus avoiding intimal 
thickening responsible for vessel obstruction (10-12). 
Moreover, the nature of the differential modes of 
action described for cyclosporine and rapamycin has led 
to the discovery of synergistic interaction between the 
two agents, suggesting potential combination use of 
both for clinical transplantation (13-15). Although the 
efficacy of rapamycin has been demonstrated after 
parenteral administration of the agent, difficulties 
have been encountered in the search for an effective 
oral formulation with good bioavailability and 
predictability (16-18). American Home Products is 
planning to submit an NDA for sirolimus as a treatment 
for immune-related anemia, using NanoCrystal 
technology from NanoSystems for delivery (19).

     During the last years, intensive research efforts 
have focused on the design of new rapamycin analogs. 
According to the Prous Science Ensemble database, 
Abbott, American Home Products, Merck & Co., Novartis, 
Pfizer and SmithKline Beecham have been involved in 
the search for this type of compounds. SDZ-RAD is one 
such rapamycin analog that maintains the 
immunosuppressive activity and pharmacological 
properties of rapamycin. SDZ-RAD has been selected for 
further development for combination use with cyclosporine 
to prevent acute and chronic rejection following solid 
organ allotransplantation.
     Pharmacological Actions

     SDZ-RAD was shown to have a differential mode of 
action as compared to cyclosporine A and FK-506 in that 
it inhibited growth factor- stimulated proliferation of 
a lymphoid cell line and VSMC. When compared to 
rapamycin in vitro, results showed that SDZ-RAD 
inhibition of IL-6-stimulated proliferation of a 
IL-6-dependent hybridoma clone...