Steroidal C-21 mercapto derivatives as dissociated steroids: discovery of an inhaled dissociated steroid.
Biju P, McCormick K, Aslanian R, Berlin M, Solomon D, Chapman R, McLeod R, Prelusky D, Eckel S, Kelly G, Natiello M, House A, Fernandez X, Bitar R, Phillips J, Anthes J.
A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.