Targeting Irritable Bowel Syndrome (IBS) with astressins

使用 astressins 治疗肠易激综合症 (IBS)

• 批准号: 9925223
• 负责人: DOMINIC BEHAN
• 金额: $ 87.51万
• 依托单位: SENTIA MEDICAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925223
• 关键词: Abdominal Pain; Acute; Address; Adult; Affect; Animals; Binding Proteins; Biological Assay; Biological Availability; Biotechnology; CRF receptor type 1; Canis familiaris; Cardiotoxicity; Cells; Chronic; Clinical; Clinical Research; Colon; Constipation; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cytochrome P450; Data; Detection; Diarrhea; Disease; Disease model; Dose; Drug Kinetics; Enteral; Enterochromaffin Cells; Evaluation; Fruit; Funding; Future; G-Protein-Coupled Receptors; Gastrointestinal tract structure; Generations; Goals; Habits; Hepatocyte; Homeostasis; Human; Hypersensitivity; In Vitro; Injectable; Intellectual Property; Intestines; Ion Channel; Irritable Bowel Syndrome; Isotope Labeling; Legal patent; Maintenance; Maximum Tolerated Dose; Measurement; Mediating; Medical; Methods; Modality; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Oral; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phenotype; Plasma; Play; Population; Preparation; Process; Production; Quality of life; Rattus; Reaction; Recurrence; Regulation; Research; Role; Safety; Science; Signal Transduction; Small Business Innovation Research Grant; Stress; Structural defect; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Tissue Extracts; Toxic effect; Toxicology; Translating; Visceral; Visceral pain; Work; astressin; base; biological adaptation to stress; clinical candidate; clinical development; design; drug candidate; drug metabolism; in vivo; mast cell; method development; novel; peptide analog; peptide drug; peptide hormone; pre-clinical; prophylactic; receptor; safety assessment; scale up; screening; side effect; small molecule

Abstract Sentia seeks to bring to fruition 40 years (1975 - 2015) of NIDDK-funded (P01 DK026741; PIs: W. Vale, C. Rivier, J. Spiess and J. Rivier) academic research to achieve translational drug candidacy by blocking both corticotropin-releasing factor (CRF) receptors CRF1/2 with potent astressin peptide antagonists. Present assets of Sentia include world-wide, patent-protected, "first-in-class" peptide drug candidates and intellectual property that targets, among others, the regulation of the stress response system. Scientific evidence documents that potentially dozens of current human ailments can benefit from the use of stress-neutralizing compounds to achieve temporal or permanent homeostasis. In particular, irritable bowel syndrome (IBS) is well established to be a stress-sensitive condition with visceral pain being the hallmark. Alleviating visceral pain in IBS patients is still an unmet need and the market for managing and/or curing the symptoms is conservatively estimated to be in the $5-10B range. Astressin therapeutics would represent a "first-in-class" opportunity to safely and effectively treat IBS patients with injectable peptide analogs that could represent a paradigm shift in therapeutic intervention away from conventional short-acting oral small molecules providing patients a different option for long-acting relief. In our Phase I SBIR studies, a new Fmoc synthetic process for making astressins was successfully validated and activity of these drug candidates was demonstrated after acute testing in an IP CRF-induced model of visceral hypersensitivity. The objective of the Phase II SBIR is to further supply relevant quantities of astressin CRF1/2 antagonists (compounds 1-3) manufactured following the Fmoc strategy to support non-GLP chronic pharmacology studies and to evaluate the drug metabolism and pharmacokinetic (DMPK) and toxicological profile of the compounds. In Aim 1, additional quantities of astressins required for the proposed non-GLP studies will be synthesized. Synthetic methods will be transferred to a CRO in preparation for future larger scale synthesis. The goal of Aim 2 will be to develop bioanalytical methods for detection of the astressin drug candidate as well as to establish the DMPK profile of the compounds and Aim 3 will evaluate the chronic efficacy of the astressin drug candidates in both prophylactic and therapeutic modalities in a pharmacological and disease model of IBS, respectively. Aim 4 will assess the in vivo and in vitro toxicological profile after acute and repeat dosing. The data package will provide sufficient information on efficacy and therapeutic margins to select a candidate(s) for further evaluation, IND-enabling studies and clinical development.

摘要 森蒂亚寻求实现40年（1975 - 2015年）的NIDDK资助（P01 DK 026741; PI：W。瓦莱角 Rivier，J. Spiess和J. Rivier）的学术研究，以通过阻断两种药物来实现转化药物候选资格。 促肾上腺皮质激素释放因子（CRF）受体CRF 1/2与强效的astressin肽拮抗剂。本 Sentia的资产包括世界范围的，受专利保护的，“一流的”肽候选药物和知识产权。 该特性尤其针对应激反应系统的调节。科学证据 文件表明，目前可能有几十种人类疾病可以受益于使用压力中和 化合物以实现暂时或永久的体内平衡。特别是，肠易激综合征（IBS） 被证实是一种压力敏感性疾病，以内脏疼痛为标志。减轻内脏疼痛 IBS患者仍然是一个未满足的需求，管理和/或治愈症状的市场是保守的 估计在50 - 100亿美元的范围内。Astressin疗法将代表一个“一流”的机会， 用可注射的肽类似物安全有效地治疗IBS患者， 治疗干预远离传统的短效口服小分子，为患者提供不同的 选择长期缓解。在我们的I期SBIR研究中， 在IP中进行急性试验后，成功验证了这些候选药物的活性 CRF诱导的内脏高敏感性模型。第二阶段SBIR的目标是进一步提供相关 按照Fmoc策略制备的一定量的astressin CRF 1/2拮抗剂（化合物1-3）， 支持非GLP慢性药理学研究，并评价药物代谢和药代动力学 （DMPK）和化合物的毒理学特征。在目标1中， 将综合拟定的非GLP研究。合成方法将在制备过程中转移给CRO 用于未来更大规模的合成。目标2的目标将是开发检测微生物的生物分析方法。 astressin候选药物以及建立化合物的DMPK谱，目标3将评估 本发明的目的是为了评估在一个受试者中，在预防性和治疗性模式中， IBS的药理学和疾病模型。目的4将评估体内和体外毒理学 急性和重复给药后的曲线。数据包将提供关于疗效的充分信息， 选择候选药物进行进一步评价的治疗范围，IND使能研究和临床 发展