PRO-DRUGS FOR LAQUINIMOD AND CONGENERS

Oral Laq. penetrates the CNS in physiologic and inflammatory pathologic conditions. When oral ¹⁴C-laquinimod was administered to track its distribution to the brain and spinal cord, in rats with experimental autoimmune encephalomyelitis (EAE) and healthy rats, healthy rats showed a 7–8% Laq. distribution to the brain and spinal cord in relation to the peripheral blood concentration at 2 h post dose, while EAE rats revealed a 13% distribution of Laq. to the brain and spinal cord in relation to the peripheral blood at an hour post dose[1]. A parallel time to the peak concentration of Laq. in the peripheral blood and the CNS was identified in the EAE model.

Hence, we initiated a focused drug discovery program aimed to identify Laq. pro-drugs with improved CNS permeability and anti-inflammatory and symptomatic neuro-protective effect in EAE models. Two approaches were entertained: 1. Synthesis of Laq. derivatives bearing lipophilic chemical moieties, e.g. in a form of ethers, esters, acetals, amides, carbamates and with fragments which might enable active transport into the brain, such as: sugars, AAs and NADH; 2. Design combinations of Laq. and drugs or part of drugs which are known to be active in the CNS which might result a synergistic effect with Laq..

The chemical strategies that lead to 75 NCEs derived from Laq. (Fig. above) as well as some of their ADMEPK screening results and evaluation in the EAE model will be presented. Other structures derived from Laquinimod but with modified framework/the basic skeleton of Laquinimod, will be reported also.

[1] Bruck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011; 306:173–9.