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
基本信息
- 批准号:8996043
- 负责人:
- 金额:$ 43.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Active SitesAdverse effectsAffectAftercareAnimal ModelArthralgiaBackBenznidazoleBiological AssayBiological AvailabilityBloodBlood specimenBrazilCanis familiarisCardiacCaspaseCathepsinsCell LineCellsCessation of lifeChagas DiseaseChronic PhaseChronic Phase of DiseaseClinicClinicalClinical ResearchClinical TrialsCollaborationsContractsControl GroupsCysteine Proteinase InhibitorsDataDegenerative polyarthritisDevelopmentDiseaseDisease modelDoseDrug ControlsDrug KineticsEnzyme InhibitionEnzymesEstersEvaluationFutureGoalsGrantHeart failureHourHumanImmunosuppressionIn VitroInfectionInternational AgenciesLatin AmericaLondonLuc GeneMedicineModelingMolecular TargetMusMuscle CellsNational Institute of Allergy and Infectious DiseaseNeuropathyNifurtimoxOralParasitesParasitic DiseasesPathologyPatientsPeptide HydrolasesPharmaceutical PreparationsPharmacologic SubstancePhasePhase I Clinical TrialsPlasmaPrimatesProtocols documentationRattusRecruitment ActivityResearchRodentSafetySerologic testsShapesSiteSouth AmericaStagingSyndromeTarget PopulationsTechniquesTestingTimeToxicologyTranslatingTrypanosoma cruziUnited StatesUniversitiesValidationanimal databasechronic paincruzipainhealthy volunteerhuman diseaseimaging systemin vitro Modelin vivo imagingindustry partnerinflammatory neuropathic paininhibitor/antagonistinnovationmouse modelneglected tropical diseasesnovelphase 1 studyposaconazolepre-clinicalpreventprogramspublic health relevancetargeted treatment
项目摘要
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。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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James H. McKerrow其他文献
Binding Mode and Potency of N-Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51
N-吲哚氧吡啶基-4-氨基丙基抑制剂针对克氏锥虫 CYP51 的结合模式和效力
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:7.3
- 作者:
D. F. Vieira;Jun Yong Choi;C. M. Calvet;J. Siqueira;Jonathan B. Johnston;Danielle Kellar;Jiri Gut;Michael D. Cameron;James H. McKerrow;William R. Roush;L. Podust - 通讯作者:
L. Podust
Elastases and elastin degradation.
弹性蛋白酶和弹性蛋白降解。
- DOI:
10.1038/jid.1982.28 - 发表时间:
1982 - 期刊:
- 影响因子:0
- 作者:
Z. Werb;M. J. Banda;James H. McKerrow;R. Sandhaus - 通讯作者:
R. Sandhaus
Giardia lamblia cysteine proteases
- DOI:
10.1007/s00436-006-0149-4 - 发表时间:
2006-04-06 - 期刊:
- 影响因子:2.000
- 作者:
Kelly N. DuBois;Marla Abodeely;Mohammed Sajid;Juan C. Engel;James H. McKerrow - 通讯作者:
James H. McKerrow
Proteinase production by the parasitic cycle of the pathogenic fungus Coccidioides immitis
病原真菌粗球孢子菌寄生循环产生的蛋白酶
- DOI:
- 发表时间:
1987 - 期刊:
- 影响因子:3.1
- 作者:
Steven Resnick;Demosthenes Pappagianis;James H. McKerrow - 通讯作者:
James H. McKerrow
Cloning of a cysteine protease required for the molting of <em>Onchocerca volvulus</em> third stage larvae.
- DOI:
10.1016/s0021-9258(19)67340-0 - 发表时间:
1997-02-14 - 期刊:
- 影响因子:
- 作者:
Sara Lustigman;James H. McKerrow;Kashmira Shah;Jing Lui;Tellervo Huima;Matt Hough;Betsy Brotman - 通讯作者:
Betsy Brotman
James H. McKerrow的其他文献
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{{ truncateString('James H. McKerrow', 18)}}的其他基金
HYDROLYSIS OF HEMOGLOBIN BY SCHISTSOMA MANSONI CATHEPSIN B-LIKE CYSTEINEPROTEASE
曼氏血吸虫组织蛋白酶 B 样半胱氨酸蛋白酶水解血红蛋白
- 批准号:
8363752 - 财政年份:2011
- 资助金额:
$ 43.82万 - 项目类别:
STRUCTURE BASED DRUG DESIGN FOR TREATMENT OF PARASITIC AND VIRAL DISEASES
用于治疗寄生虫和病毒性疾病的基于结构的药物设计
- 批准号:
8363751 - 财政年份:2011
- 资助金额:
$ 43.82万 - 项目类别:
GIARDIA LAMBLIA CYSTEINE PROTEASES: TRAFFICKING, LOCALIZATION, AND FUNCTION
贾第鞭毛虫半胱氨酸蛋白酶:运输、定位和功能
- 批准号:
8363757 - 财政年份:2011
- 资助金额:
$ 43.82万 - 项目类别:
PROTEOMICS ANALYSIS OF SCHISTOSOME HOST-INVASION AND METABOLISM
血吸虫宿主入侵和代谢的蛋白质组学分析
- 批准号:
8363754 - 财政年份:2011
- 资助金额:
$ 43.82万 - 项目类别:
GIARDIA LAMBLIA CYSTEINE PROTEASES: TRAFFICKING, LOCALIZATION, AND FUNCTION
贾第鞭毛虫半胱氨酸蛋白酶:运输、定位和功能
- 批准号:
8169751 - 财政年份:2010
- 资助金额:
$ 43.82万 - 项目类别:
HYDROLYSIS OF HEMOGLOBIN BY SCHISTSOMA MANSONI CATHEPSIN B-LIKE CYSTEINEPROTEASE
曼氏血吸虫组织蛋白酶 B 样半胱氨酸蛋白酶水解血红蛋白
- 批准号:
8169746 - 财政年份:2010
- 资助金额:
$ 43.82万 - 项目类别:
STRUCTURE BASED DRUG DESIGN FOR TREATMENT OF PARASITIC AND VIRAL DISEASES
用于治疗寄生虫和病毒性疾病的基于结构的药物设计
- 批准号:
8169745 - 财政年份:2010
- 资助金额:
$ 43.82万 - 项目类别:
Lead Identification to Clinical Candidate Selection: Drugs for Chagas Disease
临床候选药物选择的线索识别:恰加斯病药物
- 批准号:
8107529 - 财政年份:2010
- 资助金额:
$ 43.82万 - 项目类别:
Lead Identification to Clinical Candidate Selection: Drugs for Chagas Disease
临床候选药物选择的线索识别:恰加斯病药物
- 批准号:
8499225 - 财政年份:2010
- 资助金额:
$ 43.82万 - 项目类别:
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