Synthesis and characterization of the selective, reversible pkcβ inhibitor (9 s)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 h,18 h-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 h)-dione, ruboxistaurin (ly333531): 12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexade cine-18,20(19H)-dione, Ruboxistaurin (LY333531)

F. Ivy Carroll; S. Mascarella; Pulumamidi A. Reddy; Anita H. Lewin; Lawrence E. Brieaddy; Anita H. Lewin; Lawrence E. Brieaddy; Jeffrey R. Deschamps; Gregory H. Imler; S. Wayne Mascarella; Pulumamidi A. Reddy; Ivy Carroll

Synthesis and characterization of the selective, reversible pkcβ inhibitor (9 s)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 h,18 h-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 h)-dione, ruboxistaurin (ly333531)

12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexade cine-18,20(19H)-dione, Ruboxistaurin (LY333531)

Lewin, A. H., Brieaddy, L., Deschamps, J. R., Imler, G. H., Mascarella, S. W., Reddy, P. A., & Carroll, F. I. (2019). Synthesis and characterization of the selective, reversible pkcβ inhibitor (9 s)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 h,18 h-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 h)-dione, ruboxistaurin (ly333531): 12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexade cine-18,20(19H)-dione, Ruboxistaurin (LY333531). ACS Chemical Neuroscience, 10(1), 246-251. https://doi.org/10.1021/acschemneuro.8b00196

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Abstract

The demonstrated role of PKCβ in mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9 S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole.