Pii: S0968-0896(99)00045-0

نویسندگان

  • Laurent Gil
  • Yongxin Han
  • Evan E. Opas
  • Gideon A. Rodan
  • Gregory Seedor
  • Peter C. Tyler
  • Robert N. Young
  • Derek H. R. Barton
چکیده

ÐConjugates of bisphosphonates (potential bone resorption inhibitors) and prostaglandin E2 (a bone formation enhancer) were prepared and evaluated for their ability to bind to bone and to liberate, enzymatically, free PGE2. The conjugate 3, an amide at C-1 of PGE2 proved to be too stable in vivo while conjugate 6, a thioester, was too labile. Several PGE2, C-15 ester-linked conjugates (18, 23, 24 and 31) were prepared and conjugate 23 was found to bind e€ectively to bone in vitro and in vivo and to liberate PGE2 at an acceptable rate. A 4-week study in a rat model of osteoporosis showed that 23 was better tolerated and more e€ective as a bone growth stimulant than daily maximum tolerated doses of free PGE2. # 1999 Elsevier Science Ltd. All rights reserved.

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تاریخ انتشار 1999