Antiarthritic and suppressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents.
Spirogermanium (1; 8,8-diethyl-N,N-dimethyl-2-aza-8- germaspiro[4.5]decane-2-propanamine dihydrochloride) is a potent cytotoxic agent in vitro which has demonstrated limited activity in experimental animal tumor models. Subsequently, it has been reported that spirogermanium has antiarthritic and suppressor cell-inducing activity. We have synthesized a series of substituted 8-hetero-2-azaspiro[4.5]decane and 9-hetero-3-azaspiro[5.5]undecane analogues of spirogermanium to identify the heteroatom requirements for in vivo antiarthritic and suppressor cell-inducing activity. This structure-activity relationship study has identified that appropriately substituted silicon and carbon analogues of spirogermanium retain both antiarthritic and immunosuppressive activity, with the 8,8-dipropyl (carbon) analogue being among the most active. Following the identification of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride (9) as a more active analogue than spirogermanium, a series of 8,8-dipropyl analogues with various amine substituents were synthesized. A number of these analogues had activity similar to that of 9. A correlation between activity in the adjuvant arthritic rat and the ability to induce suppressor cells (r = 0.894, p less than 0.001) suggests an association between the two pharmacologic effects. While the precise biochemical mechanism(s) for the pharmacological activity is unclear, these data suggest that compounds within this series, e.g., N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride, may provide effective therapy in diseases of autoimmune origin and/or the prevention of rejection in tissue transplantation.
Badger
A M
AM
Department of Immunology, SmithKline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Schwartz
D A
DA
Picker
D H
DH
Dorman
J W
JW
Bradley
F C
FC
Cheeseman
E N
EN
DiMartino
M J
MJ
Hanna
N
N
Mirabelli
C K
CK
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D001372:Aza Compounds; D007166:Immunosuppressive Agents; D009942:Organometallic Compounds; D013141:Spiro Compounds; C062162:SK&F 105685; C026818:spirogermanium