ct2D Adrenergic agonists are used in clinic for treatment of severe pain. Following early identification of potent lead compound (Imidazolemethyl)thiophene 35, a series of compounds 36-40 were designed to restrict the rotation of the two single bonds between the imidazole and thiophene (31,32). These compounds are all very potent a2D adrenergic receptor ligands. Among them, 38 showed in vivo efficacy upon oral dosing. Compound 39 is the most potent a2o ligand with Ki of 0.009 nM, and more than 10,000-fold separation against ai. These analogs are useful pharmacological tools for studies involving the <x2d adrenergic receptor.
Transplant rejection is substantially dependent on the immuno-response of antibody production mediated by B-cells independent of T-cell signals. Leflunimide 41 is a pro-drug which converts to hydroxypropenamide in vivo and in vitro quantitatively in the cellular system. The resulting hydroxypropenamide inhibits dihydrooroate dehydrogenase (DHODH) at low concentrations, but can operate by additional protein tyrosine kinase related mechanisms at its therapeutically relevant concentrations. Hydroxypropenamide has two conformers 42 and 43 and no information is available on the DHODH-bound conformation of 42. Prazole 44 was initially designed to mimic 42 and the inhibitory activity of DHODH is similar to leflunimide (33). Compound 45 was then designed to mimic the conformer 43 (34). Compound 45 has negligible enzyme activity, however, it was found to be a highly potent and selective B-cell immunosuppressant over T-cells. Additionally, compound 45 effectively suppressed rejection in the antibody- mediated mouse xenograft model using 0.3mg/kg oral once-daily dosing.
Was this article helpful?