Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases

Abstract

Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound 34 was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound 34 displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings.

Keywords

• disease progression modeling
• phosphodiesterase inhibitors
• rheumatoid arthritis
• multiple sclerosis
• autoimmune hepatitis