Dihydroceramide Desaturase-1 Inhibitors for Treatment of Diabetes and Other Metabolic Diseases

用于治疗糖尿病和其他代谢性疾病的二氢神经酰胺去饱和酶 1 抑制剂

• 批准号: 9789254
• 负责人: Jeremy Blitzer
• 金额: $ 75万
• 依托单位: POTRERO HILL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789254
• 关键词: Address; American; Anabolism; Animals; Atherosclerosis; Binding Proteins; Biological Assay; Biological Availability; Blindness; Blood; Blood Glucose; Body Weight; C57BL/6 Mouse; Caco-2 Cells; Canis familiaris; Capital; Cardiovascular Diseases; Cells; Ceramides; Chemicals; Clinic; Clinical; Clinical Chemistry; Clinical Pathology; Clinical Trials; Coagulation Process; Comorbidity; Cytochrome P450; Development; Diabetes Mellitus; Diagnostic tests; Disease; Dose; Drug Exposure; End stage renal failure; Enzymes; Epidemic; FDA approved; Fasting; Fatty Liver; Funding; Genetic study; Glucose tolerance test; Grant; Hematology; Hep3B; Hepatocyte; High Fat Diet; Histopathology; Human; Hyperglycemia; Hypertriglyceridemia; Immunoblotting; Impaired fasting glycaemia; In Vitro; Incidence; Insulin; Insulin Resistance; Intellectual Property; Laboratories; Lead; Liver; Liver Failure; Liver Microsomes; Lymphocyte; Metabolic; Metabolic Diseases; Monitor; Mus; Myocardial Infarction; No-Observed-Adverse-Effect Level; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obese Mice; Oral; Organ; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Phenotype; Phosphorylation; Plasma; Plasma Proteins; Population; Prediabetes syndrome; Prevalence; Protocols documentation; Rattus; Risk; Rodent; Safety; Series; Skeletal Muscle; Small Business Innovation Research Grant; Solubility; Stains; Stroke; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Utah; Validation; Work; aqueous; base; blood lipid; clinical candidate; clinical development; desaturase; dihydroceramide; dihydroceramide desaturase; efficacy testing; first-in-human; food consumption; genome wide association study; in vivo; inhibitor/antagonist; lead candidate; limb amputation; liquid chromatography mass spectrometry; micronucleus; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel diagnostics; novel therapeutics; pharmacodynamic biomarker; pre-clinical; receptor; safety assessment; safety study; small molecule inhibitor; trend

Despite the current FDA-approved therapies, the prevalence of type 2 diabetes (T2D) and various other metabolic diseases is reaching epidemic proportions. Globally, 387 million people have overt diabetes, and the prevalence of impaired fasting glucose (precursor to T2D referred to as “pre-diabetes”) is 26% of the US population. Consequently, T2D and its frequent co-morbidities (high triglycerides, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis [NAFLD/NASH], and cardiovascular disease) increasingly account for a large proportion of global end-stage renal and liver failure, limb amputations, blindness, myocardial infarctions, and strokes. To address this highly unmet need, Potrero Hill Therapeutics (“PHT”) has discovered highly- potent, drug-like, and orally-active small molecule inhibitors of dihydroceramide desaturase-1 (DES1), a key enzyme which catalyzes the final step in the de novo formation of ceramides, molecules which drive insulin resistance, high triglycerides, fatty liver, and atherosclerosis when produced in excess. This work has been partially funded through an SBIR Phase 1 grant, and in this Phase 2 grant, PHT will continue preclinical characterization and early development of its lead DES1 inhibitor candidate: 1) We will comprehensively profile the therapeutic activity of our lead DES1 inhibitor candidate in a well-validated mouse model of insulin resistance/T2D, and compare its potency to those of several other candidate DES1 inhibitors; 2) We will conduct pilot safety studies of our most potent DES1 inhibitor candidate in order to determine safety margins and identify potential off-target activities; and 3) We will continue medicinal chemistry to generate several backup DES1 inhibitors. Ultimately, successful completion of these aims will yield a clinical development candidate that is ready for IND-enabling activities, including GMP manufacturing and pivotal GLP toxicology/safety studies, paving the way for clinical trials in humans.

尽管目前采用了FDA批准的疗法，但2型糖尿病的患病率（T2D）和其他各种 代谢疾病正在达到流行比例。在全球范围内，有3.87亿人患有明显的糖尿病， 禁食葡萄糖受损的患病率（称为“糖尿病前期”的T2D前体）是美国的26％ 人口。因此，T2D及其经常合并症（高甘油三酸酯，非酒精脂肪肝 疾病 /非酒精性脂肪性肝炎[NAFLD / NASH]和心血管疾病）越来越多地解释 全球末期肾脏和肝衰竭，四肢截肢，失明，心肌梗死，大部分的比例 和笔触。为了满足这种高度未满足的需求，Potrero Hill Therapeutics（“ PHT”）发现 二氢氧疗法酶抑制剂1（DES1）的有效，类似药物和口服的小分子抑制剂，钥匙 促进神经酰胺的从头形成的最后一步的酶，驱动胰岛素的分子 过量产生时耐药性，高甘油三酸酯，脂肪肝和动脉粥样硬化。这项工作已经 通过SBIR 1阶段资助部分资助，在这阶段2赠款中，PHT将继续临床前 表征和早期开发其铅DES1抑制剂候选者：1）我们将全面介绍 我们的铅DES1抑制剂候选者的治疗活性在胰岛素的验证小鼠模型中 阻力/T2D，并将其效力与其他几种候选抑制剂的效力进行比较； 2）我们会的 为了确定安全边缘，对我们最潜在的DES1抑制剂候选者进行试验安全研究 并确定潜在的非目标活动； 3）我们将继续医学化学以产生几个 备份DES1抑制剂。最终，这些目标的成功完成将产生临床发展 候选人准备进行辅助活动，包括GMP制造和关键GLP 毒理学/安全研究，为人类的临床试验铺平了道路。