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

 性状（由申请方提供）：SAR 114137是人和鼠组织蛋白酶S和K酶的强效可逆抑制剂（Ki：6 nM）。它是由赛诺菲制药公司开发的，用于治疗慢性疼痛（骨关节炎，神经性，腰痛）。SAR 114137在关节疼痛、神经性疼痛和炎性疼痛的多种动物模型中具有口服活性。该化合物具有理想的药代动力学特征，在大鼠中单次口服（PO）50 mg/kg后迅速吸收，达到最大血浆浓度的时间（tmax）为给药后0.25小时，绝对生物利用度为98%。毒理学研究表明，在大鼠中2000 mg/kg剂量和在犬中1000 mg/kg剂量不会致死。在大鼠中未观察到重大副作用。在低于1000 mg/Kg的剂量下，在犬中观察到相似的安全性。 恰加斯病是拉丁美洲心力衰竭的主要原因，也是美国的一种新感染。由于对该疾病的不确定和慢性期的疗效存在争议，以及目前用于治疗的两种含硝基药物（硝呋替莫和苄硝唑）的不可接受的副作用，目前对恰加斯病的治疗被认为是不充分的。国际机构和救援组织一致认为，需要针对T。克氏锥虫病的病原体。不幸的是，恰加斯病主要影响世界贫困地区的穷人，因此被认为是一种“被忽视的热带病”。这笔赠款代表了一个独特的机会，与加州大学圣地亚哥分校和巴西圣保罗大学的寄生虫疾病发现和创新中心（www.cdipd.org）合作，赛诺菲制药公司已同意提供一种组织蛋白酶S抑制剂，该抑制剂以前已到达诊所。克氏锥虫中组织蛋白酶S抑制剂的靶标是主要寄生虫蛋白酶cruzain（cruzipain）。一种“原理证明”半胱氨酸蛋白酶抑制剂（K777）已经证明了在啮齿动物和狗感染模型中以口服可用且安全的剂量治愈疾病和预防心脏表现的能力。然而，K777是一种迈克尔受体乙烯砜，导致对酶靶标的不可逆抑制。优选非共价抑制剂，例如Sanofi Pharmaceuticals的拟定NCATS化合物SAR 114137。值得注意的是，K777最初是作为组织蛋白酶S抑制剂合成的，但由于在人类疾病模型中缺乏疗效，该计划被放弃。在啮齿类动物、犬和灵长类动物中对该抑制剂进行的广泛评价证实了可接受的PK参数和安全性（未发表数据）。 我们的目标人群将是“不确定”（慢性）期的恰加斯病患者。这些患者在查加斯病的PCR检测中呈阳性，但尚未出现疾病的显著临床表现。我们的目标是根除现有的寄生虫，以避免未来病理学的可能性，包括心力衰竭或消化综合征。

 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.