Bronchopulmonary Dysplasia Drug Therapy

支气管肺发育不良药物治疗

基本信息

批准号：
6584534
负责人：
DEAN YOSHIMASA MAEDA
金额：
$ 16.33万
依托单位：
SYNTRIX BIOSYSTEMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-17 至 2004-01-17
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Neutrophils are bloodborne inflammatory cells that exhibit potent oxidative and phagocytic activities. One important component of the neutrophils' role in the immune system is its ability to migrate rapidly towards sites of inflammation in a process known as chemotaxis. Chemotaxis is mediated through numerous chemotactic factors that include IL-8 and Gro-alpha interacting with the neutrophil receptors CXCR1 and CXCR2. Improper and heightened neutrophil recruitment is a hallmark of several inflammatory diseases that include bronchopulmonary dysplasia in neonates subjected to mechanical ventilation with supplemental oxygen. We are developing a potent series of novel and proprietary chemotaxis inhibitors known as the nicotinamide thioglycolate esters to treat bronchopulmonary dysplasia. While initial screening identified several nicotinamide thioglycolate esters that potently inhibited chemotaxis (IC50 < 40 nM), their mechanism of inhibition is enigmatic. To further advance this promising therapeutic class, additional research is required to define their exact mechanism of action. This Phase I/II Fast-Track proposal is aimed at defining the pharmacology and pharmaceutics of these novel chemotaxis inhibitors. In Phase I, we aim to identify whether the site of action is at CXCR1 and/or CXCR2, or less likely, at the natural ligand Gro-alpha. We then aim to show that the site of action is either intracellular or extracellular. Defining the mechanism of inhibition in Phase I will establish the feasibility of proceeding to Phase II, where we aim to precisely identify the site of action at the molecular level, define and optimize their pharmaceutics, and establish efficacy in an animal model of bronchopulmonary dysplasia. The market for these therapeutic compounds is estimated to be $50 million annually in the U.S.

描述（由申请人提供）：中性粒细胞是表现出有效氧化和吞噬活性的血源性炎症细胞。中性粒细胞在免疫系统中的作用的一个重要组成部分是它在称为趋化性的过程中迅速迁移到炎症部位的能力。趋化性是通过许多趋化因子介导的，包括IL-8和GRO-ALPHA与中性粒细胞受体CXCR1和CXCR2相互作用。中性粒细胞募集不当和增强是几种炎症性疾病的标志，其中包括在接受补充氧气的机械通气的新生儿中支气管肺发育异常。我们正在开发一系列有效的新型和专有趋化性抑制剂，称为烟酰胺硫甘氨酸酯酯，以治疗支气管肺发育不良。虽然初始筛选确定了有效抑制趋化性（IC50 <40 nm）的几种烟酰胺硫甘氨酸酯酯，但它们的抑制作用是神秘的。为了进一步促进这一有希望的治疗类别，需要进行额外的研究来定义其确切的作用机理。该阶段I/II快速轨道提案旨在定义这些新型趋化性抑制剂的药理学和药物。在第一阶段，我们旨在确定动作部位是在CXCR1和/或CXCR2处，还是在天然配体α上的可能性较小。然后，我们的目的是表明作用部位是细胞内或细胞外的。定义阶段I中抑制的机制将建立前往II期的可行性，我们旨在精确地确定分子水平上的作用部位，定义和优化其药物，并在支气管肺间xplasia动物模型中建立功效。这些治疗化合物的市场估计在美国每年为5000万美元

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（12）

Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability.

DOI：
10.1016/j.bmcl.2015.07.090
发表时间：
2015-09-15
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Schuler AD;Engles CA;Maeda DY;Quinn MT;Kirpotina LN;Wicomb WN;Mason SN;Auten RL;Zebala JA
通讯作者：
Zebala JA

Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.

DOI：
10.1016/j.bmcl.2015.04.041
发表时间：
2015-06-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Maeda, Dean Y.;Peck, Angela M.;Schuler, Aaron D.;Quinn, Mark T.;Kirpotina, Liliya N.;Wicomb, Winston N.;Auten, Richard L.;Gundla, Rambabu;Zebala, John A.
通讯作者：
Zebala, John A.

Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2.

DOI：
10.1021/jm500827t
发表时间：
2014-10-23
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Maeda DY;Peck AM;Schuler AD;Quinn MT;Kirpotina LN;Wicomb WN;Fan GH;Zebala JA
通讯作者：
Zebala JA