MEDI 3 |
| The developing World is desperate for new, safe, effective and affordable antimalarial drugs and has been since the demise of chloroquine (CQ) due to PfCRT mediated parasite resistance emergence in the 60's. The talk will provide an overview of recent developments in the medicinal chemistry of 4-aminoquinoline antimalarials and will then focus on the Isoquine series of 4-aminoquinolines. Using the 4-aminoquinoline amodiaquine (AQ) as our template we have developed simple routes to novel rationally designed analogues that are highly effective against CQ resistant parasites. Importantly these are not metabolized to substrates for the resistance mechanism and cannot form reactive electrophilic quinoneimine metabolites associated with the drug-induced hepatotoxicity and agranulocytosis seen in humans taking amodiaquine. Interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine blocks quinoneimine formation and replacement of the diethylamino side chain with a t-butyl group blocks P450 mediated dealkylation to metabolites displaying cross resistance with CQ and retains the key physiochemical features of the parent drug required for activity against CQR parasites. GSK369796 was candidate selected based on excellent activity against human malaria P.falciparum isolates in vitro and rodent malaria parasites in vivo and an optimised synthetic route that delivered this novel synthetic quinoline in a two-step procedure from cheap and available starting materials. The molecule has a full industry standard pre-clinical development programme allowing first into man to proceed in 2007. Employing CQ and AQ as comparator molecules in the pre-clinical plan, the first pre-clinical dossier of GLP pharmacokinetic, toxicity and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. |
|
Antimalarial
9:00 AM-12:40 PM, Sunday, August 19, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |