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

组织蛋白酶 S 抑制剂作为恰加斯病潜在药物的评价

• 批准号: 8996043
• 负责人: James H. McKerrow
• 金额: $ 43.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996043
• 关键词: Active Sites; Adverse effects; Affect; Aftercare; Animal Model; Arthralgia; Back; Benznidazole; Biological Assay; Biological Availability; Blood; Blood specimen; Brazil; Canis familiaris; Cardiac; Caspase; Cathepsins; Cell Line; Cells; Cessation of life; Chagas Disease; Chronic Phase; Chronic Phase of Disease; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Contracts; Control Groups; Cysteine Proteinase Inhibitors; Data; Degenerative polyarthritis; Development; Disease; Disease model; Dose; Drug Controls; Drug Kinetics; Enzyme Inhibition; Enzymes; Esters; Evaluation; Future; Goals; Grant; Heart failure; Hour; Human; Immunosuppression; In Vitro; Infection; International Agencies; Latin America; London; Luc Gene; Medicine; Modeling; Molecular Target; Mus; Muscle Cells; National Institute of Allergy and Infectious Disease; Neuropathy; Nifurtimox; Oral; Parasites; Parasitic Diseases; Pathology; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Primates; Protocols documentation; Rattus; Recruitment Activity; Research; Rodent; Safety; Serologic tests; Shapes; Site; South America; Staging; Syndrome; Target Populations; Techniques; Testing; Time; Toxicology; Translating; Trypanosoma cruzi; United States; Universities; Validation; animal data; base; chronic pain; cruzipain; healthy volunteer; human disease; imaging system; in vitro Model; in vivo imaging; industry partner; inflammatory neuropathic pain; inhibitor/antagonist; innovation; mouse model; neglected tropical diseases; novel; phase 1 study; posaconazole; pre-clinical; prevent; programs; public health relevance; targeted treatment

 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.

 描述（由申请人提供）：SAR114137 是人和鼠组织蛋白酶 S 和 K 酶的有效且可逆的抑制剂（Ki：6nM）。它由赛诺菲制药公司开发，用于治疗慢性疼痛（骨关节炎、神经性疼痛、腰痛）。 SAR114137 在多种关节痛、神经性疼痛和炎性疼痛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，单次口服 (PO) 50 mg/kg 剂量后在大鼠中迅速吸收，给药后 0.25 小时达到最大血浆浓度 (tmax)，绝对生物利用度为 98%。毒理学研究表明，大鼠 2000 mg/kg 剂量和狗 1000 mg/kg 剂量均不会致死。在大鼠中没有观察到重大副作用。在低于 1000 毫克/公斤的剂量下，狗身上也观察到了类似的安全性。 恰加斯病是拉丁美洲心力衰竭的主要原因，也是美国的一种新出现的感染。由于对恰加斯病不确定期和慢性期疗效的争议，以及目前用于治疗的两种含硝基药物硝呋莫司和苯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够的。国际机构和救援组织一致认为，需要针对克氏锥虫（一种导致恰加斯病的原生寄生虫）的新疗法。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”(NTD)。这笔赠款代表了加州大学圣地亚哥分校寄生虫病发现与创新中心 (www.cdipd.org) 和巴西圣保罗大学与赛诺菲制药公司合作的独特机会，赛诺菲制药公司已同意提供一种先前已进入临床的组织蛋白酶 S 抑制剂。克氏锥虫组织蛋白酶 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）已被证明能够在啮齿动物和狗的感染模型中以口服且安全的剂量治愈疾病并预防心脏表现。然而，K777 是一种迈克尔受体乙烯基砜，导致对酶靶点产生不可逆的抑制。非共价抑制剂，例如赛诺菲制药公司 SAR114137 提议的 NCATS 化合物，将是优选的。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。在啮齿动物、狗和灵长类动物中对该抑制剂进行了广泛的评估，证实了可接受的 PK 参数和安全性（未发表的数据）。 我们的目标人群将是处于恰加斯病“不确定”（慢性）阶段的患者。这些患者在恰加斯病 PCR 检测中呈阳性，但尚未出现明显的疾病临床表现。我们的目标是根除现有的寄生虫，以避免未来发生病理的可能性，包括心力衰竭或消化综合症。