Inhibitors of Inosine Monophosphate Dehydrogenase

Pankiewicz, Krzysztof

Abstract

The long term objective of this research is to develop potent and selective inhibitors of Inosine Monophosphate Dehydrogenase for eventual clinical application. These targeted compounds are designed to be metabolically stable NAD analogues which should not affect other cellular dehydrogenases and should penetrate cell membranes. The specific affinity towards IMPDH (beta-specific) will be achieved by replacement of the nicotinamide riboside portion of NAD with conformationally restricted benzamide ribosides which are fixed in the """"""""syn"""""""" range required for tight binding to IMPDH. These compounds will be also improved by introduction of fluorine at 2'-position of the adenosine moiety. Fluorination at the 2' position prevents the further conversion of NAD analogues to NADP like compounds. This is important for two reasons 1) The concentration of NAD analogue will not be depleted by conversion to a different analogue. 2) The inhibition of NADP requiring enzymes may prove deleterious to cells. The cells membrane penetration will be address by synthesis of their methylene mono- and di-thiophosphonates. Since oligo phosphorothioates are known to penetrate cell membranes, the cellular up-take of these cofactor type thiophosphonates should be dramatically improved. Methylene diphosphonate analogue of NAD, called beta-methylene TAD, has already been demonstrated to enter cells. Acute and chronic myelogenous leukemias are our particular targets for these compounds which are expected to inhibit cancerous cell growth as well as to induce cell differentiation into mature cells.

Proposed Commercial Applications

IMPDH inhibitors are of interest to several drug companies. At present, only few such inhibitors have been developed but none so far found commercial application. Thus, selective, metabolically stable, cofactor- type inhibitors of IMPDH are expected to be of great therapeutic interest and commercial potential.