Manitimus

General information

Synthetic malononitrilamides have been derived from A77 1726, the active metabolite of leflunomide. Of these, manitimus (malononitrilamide 715; FK778) is the most promising, because of its much shorter half-life.

Manitimus blocks de novo pyrimidine synthesis, by inhibiting the mitochondrial enzyme dihyro-orotate dehydrogenase and tyrosine kinase [ ]. It also inhibits activation of NFκB in human dendritic cells [ ], inhibiting their differentiation, maturation, and function [ , ]. It prevents acute allograft rejection in experimental transplant models and vascular remodelling after mechanical intimal injury. In vitro, it blocks replication of herpesvirus, cytomegalovirus, and polyoma virus. It also suppresses proliferation of human lymphocytes and expression of various T cell surface antigens (CD25, CD11a, CD95, CD154) [ ]. It is being explored in studies in solid organ transplant recipients [ ].

Phase I data suggested that food has no substantial effect on the oral systemic availability of manitimus, that there is no effect of sex on its pharmacokinetics, and that very little of the unchanged drug is eliminated in the urine; there were no dose-limiting adverse reactions, despite escalation of single doses to 1100 mg and repeated doses to 200 mg/day [ ].