title: Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis.
abstract: 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.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, Merck & Co., Rahway, New Jersey 07065, USA. petr_vachal@merck.com
authors.forename: Petr
authors.initials: P
authors.lastname: Vachal
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
authors.forename: Eric C
authors.initials: EC
authors.lastname: Streckfuss
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Yin
authors.forename: Kimberly
authors.initials: K
authors.lastname: Algayer
authors.forename: Kimberly
authors.initials: K
authors.lastname: Manser
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.forename: Soumojeet
authors.initials: S
authors.lastname: Ghosh
authors.forename: Laman L
authors.initials: LL
authors.lastname: Alani
mesh_terms: 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
chemical_list: D050071:Bone Density Conservation Agents; C511629:N-myristoylalendronic acid; D011355:Prodrugs; D019386:Alendronate