Prostaglandin E2-bisphosphonate conjugates:: Potential agents for treatment of osteoporosis

Conjugates of bisphosphonates (potential bone resorption inhibitors) and prostaglandin E-2 (a bone formation enhancer) were prepared and evaluated for their ability to bind to bone and to liberate, enzymatically, free PGE(2). The conjugate 3, an amide at C-1 of PGE(2) proved to be too stable in vivo while conjugate 6, a thioester, was too labile. Several PGE(2), C-15 ester-linked conjugates (18, 23, 24 and 31) were prepared and conjugate 23 was found to bind effectively to bone in vitro and in vivo and to liberate PGE(2) at an acceptable rate. A 4-week study in a rat model of osteoporosis showed that 23 was better tolerated and more effective as a bone growth stimulant than daily maximum tolerated doses of free PGE(2). (C) 1999 Elsevier Science Ltd. All rights reserved.