Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis.
Alendronate derivatives were evaluated as potential prodrugs for the osteoporosis drug alendronate sodium in an attempt to enhance the systemic exposure after oral administration. An investigation of the chemical behavior of alendronate derivatives led to development of practical synthetic strategies and prediction of each structural class's prodrug potential. Pharmacokinetic studies of N-myristoylalendronic acid revealed that 25% have been converted in vivo after i.v. administration in rat, providing an important proof-of-concept for this strategy.
Vachal
Petr
P
Department of Basic Chemistry, Merck Research Laboratories, Merck & Co., Rahway, New Jersey 07065, USA. petr_vachal@merck.com
Hale
Jeffrey J
JJ
Lu
Zhe
Z
Streckfuss
Eric C
EC
Mills
Sander G
SG
MacCoss
Malcolm
M
Yin
Daniel H
DH
Algayer
Kimberly
K
Manser
Kimberly
K
Kesisoglou
Filippos
F
Ghosh
Soumojeet
S
Alani
Laman L
LL
D019386:Alendronate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010024:Osteoporosis / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D050071:Bone Density Conservation Agents; C511629:N-myristoylalendronic acid; D011355:Prodrugs; D019386:Alendronate