Design and synthesis of 13,14-dihydro prostaglandin F(1alpha) analogues as potent and selective ligands for the human FP receptor.
The in vitro evaluation of a new class of potential bone anabolic agents for the treatment of osteoporosis is described. These compounds are potent and selective ligands for the human prostaglandin F receptor (hFP receptor). The compounds lack the olefin unsaturation required for potency in the natural ligand PGF(2)(alpha) yet retain binding affinity for the hFP receptor in the nanomolar to micromolar range. Removal of the alkenes also results in a better selectivity ratio for the hFP receptor over the other prostaglandin receptors tested. A rationale for the selectivity differences of various analogues, based on ligand docking experiments to a putative hFP receptor model, is also described.
Wang
Y
Y
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
Wos
J A
JA
Dirr
M J
MJ
Soper
D L
DL
deLong
M A
MA
Mieling
G E
GE
De
B
B
Amburgey
J S
JS
Suchanek
E G
EG
Taylor
C J
CJ
D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010024:Osteoporosis / Q000188:drug therapy; D011460:Prostaglandins F / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008024:Ligands; D011460:Prostaglandins F; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor