Evaluation of a cathepsin S inhibitor as a potential drug for Chagas disease

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 DESCRIPTION (provided by applicant): SAR114137 is a potent and reversible inhibitor of human and murine cathepsin S and K enzymes (Ki: 6nM). It was developed by Sanofi Pharmaceuticals to treat chronic pain (osteoarthritis, neuropathic, low back). SAR114137 is orally active in numerous animal models of joint pain, neuropathic, and inflammatory pain. The compound has a desirable pharmacokinetic profile, being rapidly absorbed in rats following a single 50 mg/kg oral (PO) dose with time to reach maximum plasma concentration (tmax) of 0.25 hours post dose, and absolute bioavailability of 98%. Toxicology studies demonstrated that in rats a 2000 mg/kg dose and in dogs a 1000 mg/kg dose were not lethal. No major side effects were observed in rats. Similar safety was observed in dogs at doses below 1000mg/Kg. Chagas disease is the leading causes of heart failure in Latin America, and an emerging infection in the United States. Current therapy for Chagas disease is deemed inadequate due to controversy about efficacy in the indeterminate and chronic phases of the disease, as well as unacceptable side effects from the two nitro- containing drugs currently used for therapy: nifurtimox and benznidazole. International agencies and relief groups unanimously conclude that there is a need for new therapy targeting T. cruzi, the protozoan parasite responsible for Chagas disease. Unfortunately, Chagas disease primarily affects poor people in poor regions of the world, and is therefore considered a "neglected tropical disease" (NTD). This grant represents a unique opportunity to partner the Center for Discovery and Innovation in Parasitic Diseases (www.cdipd.org) at UCSD and the University of Sao Paulo in Brazil with Sanofi Pharmaceuticals, which has agreed to provide a cathepsin S inhibitor that has previously reached the clinic. The target for the cathepsin S inhibitor in Trypanosoma cruzi is the major parasite protease, cruzain (cruzipain). A "proof of principle" cysteine protease inhibitor (K777) has demonstrated a capacity to cure disease and prevent cardiac manifestations in rodent and dog models of infection at doses which are orally available and safe. However, K777 is a Michael-acceptor vinylsulfone, resulting in irreversible inhibition of the enzyme target. A noncovalent inhibitor, such as the proposed NCATS compound from Sanofi Pharmaceuticals SAR114137 would be preferable. Notably, K777 was originally synthesized as a cathepsin S inhibitor, but that program was abandoned due to lack of efficacy in human disease models. Extensive evaluation of this inhibitor in rodents, dogs, and primates has confirmed acceptable PK parameters and safety (unpublished data). Our target population will be patients in the "indeterminate" (chronic) phase of Chagas disease. These are the patients who are positive in PCR tests for Chagas disease but have not yet developed significant clinical manifestations of disease. Our goal is to eradicate the existing parasites to avoid the possibility of future pathology, including heart failure or digestive syndrome.