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

• 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
• 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

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）：该R01申请名为“组织非特异性碱性磷酸酶新抑制剂的先导优化”，是对PAR-12-060“体内化学探针发现的有效靶点征集”的回应。内侧血管钙化（MVC）是婴儿期广泛性动脉钙化（GACI）发病和死亡的主要原因，是一种严重的儿童疾病，并导致川崎病（KD）、慢性肾病（CKD）以及糖尿病、肥胖和衰老的心血管恶化。在这些条件下，矿化抑制剂细胞外无机焦磷酸盐（ePPi）及其稳态的相关性已经明确确立。ePPi水平的降低与组织非特异性碱性磷酸酶（TNAP）表达水平的升高有关，TNAP可水解ePPi，从而消除其在MVC受损组织中的抑制作用。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，这表明TNAP活性过高是epi缺乏和内侧钙化的重要原因。我们假设，强效的小分子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