A novel class of local antiinflammatory steroids. 2nd communication: pharmacological studies of methyl 11 beta,17 alpha,21- trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate and methyl 11 beta,21-dihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate.
Two novel 16-substituted steroidal carboxylate esters derived from prednisolone, methyl 11 beta,17 alpha,21- trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (P16CM) and methyl 11 beta,21-dihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha- carboxylate (DeoxyP16CM) were evaluated for in vivo antiinflammatory and glucocorticoid activities. Results indicate that incorporation of a methoxycarbonyl group at the 16 position of prednisolone, as in P16CM, resulted in 5.5 times more local activity in the cotton pellet granuloma assay and 14 times more topical activity in the croton oil induced ear edema bioassay as compared with the parent compound prednisolone (P). The 17 alpha-dehydroxy analogue of P16CM (DeoxyP16CM) retained one-half the local activity of P in the cotton pellet granuloma bioassay and topical activity equal to P in the croton oil induced ear edema bioassay. Favorable dissociation of local from systemic effects is seen for these steroidal 16-carboxylate esters since their systemic antiinflammatory activity was significantly less than that of P, and their suppression of plasma corticosterone and ACTH levels was minimal. While P16CM does exhibit some thymolytic activity, DeoxyP16CM is essentially devoid of thymus atrophogenic effects at equiactive doses. Thus, these compounds may represent safer topical therapeutic agents.
Heiman
A S
AS
Center for Anti-inflammatory Research, Florida A & M University College of Pharmacy, Tallahassee.
Kim
H P
HP
Taraporewala
I B
IB
Lee
H J
HJ
D000287:Administration, Topical; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001284:Atrophy / Q000139:chemically induced / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D005938:Glucocorticoids; D006003:Glycogen / Q000378:metabolism; D006099:Granuloma / Q000188:drug therapy; D008297:Male; D010998:Pleurisy / Q000188:drug therapy; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014444:Tyrosine Transaminase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; C059496:methyl 11,17,21-trihydroxy-3,20-dioxopregna-1,4-diene-16-carboxylate; D000324:Adrenocorticotropic Hormone; D006003:Glycogen; D011239:Prednisolone; D014444:Tyrosine Transaminase; D003345:Corticosterone