Lead Optimization of Novel Inhibitors of Tissue Non-specific Alkaline Phosphatase

新型组织非特异性碱性磷酸酶抑制剂的先导化合物优化

基本信息

批准号：
8727436
负责人：
Nicholas David Cosford
金额：
$ 75.24万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727436
关键词：
Affect Aging Alkaline Phosphatase Ankylosis Aorta Biological Assay Biological Availability Biological Process Blood Vessels Bone Matrix Cardiovascular system Cessation of life Chemicals Chemistry Childhood Chronic Kidney Failure Clinical Complication Congestive Heart Failure Degenerative polyarthritis Deterioration Development Diabetes Mellitus Diphosphates Disease Drug Kinetics Event Family Foundations Future Heterotopic Ossification Homeostasis Human Hypertension In Vitro Kinetics Laboratories Lead Ligaments Link Medial Metabolic Morbidity - disease rate Mucocutaneous Lymph Node Syndrome Myocardial Ischemia Neonatal Obesity Patients Permeability Pharmaceutical Preparations Physiological Plasma Positioning Attribute Production Property Protein Binding Rattus Reporting Rodent Sclerosis Series Smooth Muscle Myocytes Spinal Symptoms Testing Therapeutic Therapeutic Agents Tissues Up-Regulation Vascular Smooth Muscle Vascular calcification calcification design effective therapy extracellular high throughput screening in vitro Assay in vitro activity in vivo in vivo Model infancy inhibitor/antagonist lead series member mineralization mortality novel overexpression phosphatase inhibitor preclinical study prevent public health relevance research study response skeletal skeletal tissue small molecule small molecule libraries soft tissue subcutaneous therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): This R01 application entitled "Lead Optimization of Novel Inhibitors of Tissue Non-specific Alkaline Phosphatase" is in response to PAR-12-060 "Solicitation of Validated Hits for the Discovery of in vivo Chemical Probes". Medial vascular calcification (MVC) is the major cause of morbidity and mortality in generalized arterial calcification of infancy (GACI), a severe childhood disease, and contributes to cardiovascular deterioration in Kawasaki disease (KD), chronic kidney disease (CKD), as well as in diabetes, obesity and aging. The relevance of the mineralization inhibitor extracellular inorganic pyrophosphate (ePPi) and its homeostasis in these conditions has been clearly established. Reduced levels of ePPi have been linked to elevated expression levels of tissue non-specific alkaline phosphatase (TNAP), which hydrolizes ePPi, thus eliminating its inhibitory effect in tissue stricken by MVC. For example, we have recently observed an upregulation of TNAP in vascular smooth muscle cells (VSMC) and also in uremic aortas, suggesting that excessive TNAP activity is an important cause of ePPi deficiency and medial calcification. We hypothesized that potent small molecule TNAP inhibitors are likely to cause a reduction in TNAP activity following systemic administration, resulting in an increase in the local amount of ePPi to prevent or ameliorate vascular calcification. Therefore, we propose a strategy for increasing ePPi levels by reducing TNAP activity with small molecule TNAP inhibitors. We recently reported the characterization and preliminary optimization of arylsulfonamide-derived inhibitors of TNAP. These compounds, which function via an uncompetitive mechanism, are ready for full-scale chemistry optimization to provide lead compounds ready for in vivo proof- of-concept studies. Therefore our Specific Aims are: 1) Design and synthesize optimized TNAP inhibitors that are orally active in vivo; 2) Assess the potency and selectivity of TNAP inhibitors in relevan in vitro assays; 3) Evaluate novel small molecule TNAP inhibitors using in vitro ADME/T and in vivo pharmacokinetic (PK) assays; and 4) Characterize lead TNAP inhibitor probes in rodent ex vivo and in vivo models of vascular calcification. The TNAP inhibitors generated will provide powerful tools for testing the hypothesis that enhancing ePPi levels by modulating TNAP activity protects against MVC, while laying a foundation for future development of a novel class of medications for the treatment of the family of diseases caused by MVC.

描述（由申请人提供）：这个题为“组织非特异性碱性磷酸酶新型抑制剂的先导优化”的 R01 申请是对 PAR-12-060“体内化学探针发现的验证命中征集”的回应。内侧血管钙化 (MVC) 是婴儿期全身动脉钙化 (GACI)（一种严重的儿童疾病）发病和死亡的主要原因，并导致川崎病 (KD) 和慢性肾病 (CKD) 的心血管恶化如糖尿病、肥胖和衰老。矿化抑制剂细胞外无机焦磷酸盐 (ePPi) 及其在这些条件下的稳态的相关性已明确确定。 ePPi 水平降低与组织非特异性碱性磷酸酶 (TNAP) 表达水平升高有关，TNAP 会水解 ePPi，从而消除其在受 MVC 影响的组织中的抑制作用。例如，我们最近观察到血管平滑肌细胞（VSMC）和尿毒症主动脉中 TNAP 的上调，表明过度的 TNAP 活性是 ePPi 缺乏和内侧钙化的重要原因。我们假设强效小分子 TNAP 抑制剂可能会导致全身给药后 TNAP 活性降低，导致局部 ePPi 量增加预防或改善血管钙化。因此，我们提出了一种通过使用小分子 TNAP 抑制剂降低 TNAP 活性来提高 ePPi 水平的策略。我们最近报道了芳基磺酰胺衍生的 TNAP 抑制剂的表征和初步优化。这些化合物通过非竞争性机制发挥作用，可进行全面的化学优化，为体内概念验证研究提供先导化合物。因此，我们的具体目标是： 1）设计和合成优化的具有口服体内活性的 TNAP 抑制剂； 2) 评估TNAP抑制剂在相关体外试验中的效力和选择性； 3) 使用体外 ADME/T 和体内药代动力学 (PK) 测定评估新型小分子 TNAP 抑制剂； 4) 在啮齿动物离体和体内血管钙化模型中表征先导 TNAP 抑制剂探针。所产生的 TNAP 抑制剂将为检验通过调节 TNAP 活性提高 ePPi 水平可预防 MVC 的假设提供强大的工具，同时为未来开发一类用于治疗 MVC 引起的疾病家族的新型药物奠定基础。