Johnson Kathryn M S
Beloit College, Department of Biology, Beloit, WI 53511, USA.
Curr Opin Investig Drugs. 2010 Apr;11(4):455-63.
Dutogliptin (PHX-1149T), being developed by Phenomix Corp, Forest Laboratories Inc and Chiesi Farmaceutici SpA, is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor for the potential oral treatment of type 2 diabetes mellitus (T2DM). DPP-4 quickly degrades the insulin secretory hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1; thus inhibiting the degradation of these hormones is a viable treatment option for patients with T2DM. In preclinical studies, dutogliptin potently inhibited DPP-4 and, in a model of T2DM, treatment with dutogliptin improved glucose homeostasis. Pharmacokinetic analyses in animals, healthy individuals and patients with T2DM demonstrated that drug exposure increased in a dose-dependent manner. Results from phase II clinical trials indicated that once-daily dutogliptin, in combination with other oral diabetes therapies, reduces postprandial blood glucose and HbA1c levels, both indicators of successful diabetes management. In phase I and II trials, dutogliptin was safe, well tolerated and associated with extremely low rates of hypoglycemia. At the time of publication, phase III trials were underway and the results of these will be imperative to determine the efficacy of dutogliptin compared with other small molecule DPP-4 inhibitors, such as sitagliptin and vildagliptin.
由Phenomix公司、福瑞达医药集团公司和基耶西制药公司共同研发的度格列汀（PHX - 1149T）是一种小分子二肽基肽酶 - 4（DPP - 4）抑制剂，具有口服治疗2型糖尿病（T2DM）的潜力。DPP - 4能迅速降解胰岛素分泌激素、葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽 - 1；因此，抑制这些激素的降解是T2DM患者可行的治疗选择。在临床前研究中，度格列汀能有效抑制DPP - 4，并且在T2DM模型中，度格列汀治疗可改善葡萄糖稳态。在动物、健康个体和T2DM患者中进行的药代动力学分析表明，药物暴露量呈剂量依赖性增加。II期临床试验结果表明，每日一次的度格列汀与其他口服糖尿病治疗药物联合使用时，可降低餐后血糖和糖化血红蛋白（HbA1c）水平，这两个指标都是糖尿病管理成功的标志。在I期和II期试验中，度格列汀安全、耐受性良好，且低血糖发生率极低。在本文发表时，III期试验正在进行，这些试验的结果对于确定度格列汀与其他小分子DPP - 4抑制剂（如西他列汀和维格列汀）相比的疗效至关重要。
