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（由适用提供）：SAR114137是人和鼠组织蛋白酶和K酶（KI：6nm）的潜在和可逆抑制剂。它是由赛诺菲药物（Sanofi Pharmaceuticals）开发的，可以治疗慢性疼痛（骨关节炎，神经性，下背部）。 SAR114137在许多关节疼痛，神经性疼痛和炎症性疼痛的动物模型中口中活跃。该化合物具有理想的药代动力学特征，在单个50 mg/kg口服（PO）剂量后迅速吸收在大鼠中，剂量后达到0.25小时的最大血浆浓度（TMAX），绝对生物利用度为98％。毒理学研究表明，在2000 mg/kg剂量和狗中，1000 mg/kg剂量的剂量并非致命。在大鼠中未观察到重大副作用。狗的剂量以低于1000 mg/kg的速度观察到了类似的安全性。查加斯病是拉丁美洲心力衰竭的主要原因，也是美国新兴的感染。由于关于该疾病的不确定和慢性相的有效性以及目前使用的两种含有硝基含量的药物的不可接受的副作用，目前对查加斯疾病的治疗被认为是不足的：nifurtimox和nifurtimox和苯并尼迪唑。国际机构和救济团体一致包括，需要针对chagas病的原生动物寄生虫T. cruzi的新疗法。不幸的是，查加斯疾病主要影响了世界贫困地区的穷人，因此被认为是“被忽视的热带疾病”（NTD）。该赠款是一个独特的机会，可以将UCSD的寄生疾病发现与创新中心（www.cdipd.org）与巴西圣保罗大学与Sanofi Pharmaceuticals与Sanofi Pharmaceuticals与Sanofi Pharmaceutals与已达到临床诊所的Catherpsin抑制剂的同意。 Cruzi锥虫瘤中组织蛋白酶抑制剂的靶标是Cruzain（Cruzipain）的主要寄生虫蛋白。 “原理证明”半胱氨酸蛋白抑制剂（K777）表明，以口服可用且安全的剂量，可以治愈疾病并预防啮齿动物和狗模型的心脏表现。但是，K777是一种迈克斯型乙烯基磺酮，导致对酶靶标的不可逆抑制。非共价抑制剂，例如SANOFI Pharmaceuticals SAR114137的拟议的NCAT化合物。值得注意的是，K777最初是合成为组织蛋白酶抑制剂的，但是由于人类疾病模型缺乏效率，该程序被放弃了。对啮齿动物，狗和私人抑制剂的广泛评估已确认可接受的PK参数和安全性（未发表的数据）。我们的目标人群将是夏加斯病的“不确定”（慢性）阶段的患者。这些患者在PCR测试中呈阳性的患者，但尚未发展出疾病的临床临床表现。我们的目标是消除现有的寄生虫，以避免未来病理的可能性，包括心力衰竭或消化综合症。