18 Discovery, Mode of Action, and Commercialization of Derquantel Debra J. Woods * , Steven J. Maeder, Alan P. Robertson, Richard J. Martin, Timothy G. Geary, David P. Thompson, Sandra S. Johnson, and George A. Conder Abstract The frequent use of anthelmintics, particularly in geographic areas of intense parasite transmission, has led to the selection and spread of parasite strains that are resistant to them. Against that backdrop, Upjohn Animal Health (now Pfizer Animal Health) established a discovery program to identify compounds with novel modes of action and effective against several important nematode species, including strains resistant to the major classes of anthelmintics. This testing led to the discovery of 2-deoxy-paraherquamide (derquantel) – the first of the spiroindole class of anthelmintics with commercial utility. Derquantel was prepared semisynthetically by chemical reduction of paraherquamide, isolated from fermentation extracts of Penicillium simplicissimum. It was subsequently shown that derquantel is a nicotinic cholinergic antagonist. During clinical development, derquantel was combined with the macrocyclic lactone, abamectin. The combination of the new chemical with a second anthelmintic from a different chemical class in a single product (Startect Ò ) provides a more complete spectrum of anthelmintic activity and efficacy against resistant strains. Additionally, the combination also offers a means of minimizing selection for resistance to derquantel through the use of abamectin with a second, distinct mode of action, thereby potentially enhancing the sustainability of worm control programs. Introduction The history of chemotherapy for all forms of infectious disease has been driven primarily by the remarkable capacity of infecting organisms to develop resistance to the drugs used against them. In general, resistance develops most rapidly and profoundly when the number of drugs is limited, frequency of dosing is high, and underdosing commonly practiced. Clearly, each of these conditions characterized chemotherapy for parasitic helminths in the second half of the twentieth century. The introduction of ivermectin [1] into veterinary usage in the early 1980s * Corresponding Author. Parasitic Helminths: Targets, Screens, Drugs and Vaccines, First Edition. Edited by Conor R. Caffrey Ó 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. j297