Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.
A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.
Soper
D L
DL
Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
Milbank
J B
JB
Mieling
G E
GE
Dirr
M J
MJ
Kende
A S
AS
Cooper
R
R
Jee
W S
WS
Yao
W
W
Chen
J L
JL
Bodman
M
M
Lundy
M W
MW
De
B
B
Stella
M E
ME
Ebetino
F H
FH
Wang
Y
Y
deLong
M A
MA
Wos
J A
JA
D015502:Absorptiometry, Photon; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D019556:COS Cells; D015237:Dinoprost / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010024:Osteoporosis / Q000188:drug therapy; D010052:Ovariectomy; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014057:Tomography, X-Ray Computed; D014162:Transfection
C440616:2-decarboxy-2-(P-methylphosphinico)-16-phenoxytetranorprostaglandin F(2alpha); D010721:Phosphinic Acids; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; D015237:Dinoprost