Pharmacological evaluation of five novel dexamethasone heneicosoic (21) acid derivatives.
Five novel dexamethasone 21-oic acid derivatives (DM-I, II, IV, V and VI) were prepared from dexamethasone in accordance with the antedrug concept and their local anti-inflammatory activities and systemic untoward effects were evaluated through steroid receptor binding study, cotton pellet granuloma bioassay and acute pharmacological studies. The acetonide derivatives, DM-V and DM-VI, were found to possess much stronger affinities to glucocorticoid receptors than the acid ester derivatives, DM-I and DM-II, in vitro. In in vivo experiments, locally applied DM-V and DM-VI exerted potent inhibitory activity against granuloma formation; DM-I and DM-II also produced moderate granuloma inhibitory activity in spite of their weak affinity to the receptors. DM-II, DM-V and DM-VI manifested less systemic effects than dexamethasone, prednisolone and DM-I, such as thymus involution, suppression of plasma corticosterone and gluconeogenesis in the liver. Among the five compounds, DM-V could be exemplified as a potentially useful antedrug for topical or local application, since it has anti-inflammatory potency approaching that of the more traditional steroid prednisolone, but it does not have the systemic adverse effects.
Hong
S U
SU
Yuhan Research Center, Yuhan Corporation, Gunpo, Kyounggido, Korea.
Park
K H
KH
Chae
J S
JS
Lee
J W
JW
Kim
C S
CS
Kim
J K
JK
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003600:Cytosol / Q000378:metabolism / Q000648:ultrastructure; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008982:Molybdenum / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism / Q000648:ultrastructure; D014316:Tritium
D011965:Receptors, Glucocorticoid; D014316:Tritium; D003907:Dexamethasone; D008982:Molybdenum; C024687:sodium molybdate(VI); D003345:Corticosterone