Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.

中文翻译：

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鉴定ñ - （5-叔丁基-异恶唑-3-基） - ñ ' - {4- [7-（2-吗啉-4-基-乙氧基）咪唑并[2,1- b ] [1,3 ] benzothiazol-2-yl] phenyl} urea Dihydrochloride（AC220），一种独特的，有效的，选择性的和有效的FMS酪氨酸激酶3（FLT3）抑制剂

已经探讨了使用FLT3激酶小分子抑制剂治疗AML患者的可行方法。然而，由于缺乏足够的效力或次优的口服药代动力学（PK）或在有效剂量下缺乏足够的耐受性，发现这些药物对于AML的治疗不是最佳的。我们已经开发了一系列具有良好口服PK特性的极有效和高度选择性的FLT3抑制剂。发现以1代表的第一系列化合物（AB530）是一种有效的，选择性的FLT3激酶抑制剂，具有良好的PK特性。发现高剂量在啮齿动物中的水溶性和口服PK特性对于临床发展而言不是最佳的。设计了一系列新的化合物，这些化合物不含1的羧酰胺基加上一个增水基团。从该系列化合物中鉴定出化合物7（AC220）是最有效和选择性最强的FLT3抑制剂，在肿瘤异种移植模型中具有良好的药物特性，出色的PK特性，优异的疗效和耐受性。化合物7已证明在人体中具有理想的安全性和PK特性，目前正在II期临床试验中。