Development of a potent and orally active activator of adenosine monophosphate-activated protein kinase (AMPK), ASP4132, as a clinical candidate for the treatment of human cancer.,Bioorganic & Medicinal Chemistry

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Development of a potent and orally active activator of adenosine monophosphate-activated protein kinase (AMPK), ASP4132, as a clinical candidate for the treatment of human cancer.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-08 , DOI: 10.1016/j.bmc.2020.115307
Kazuyuki Kuramoto ₁ , Hiroyoshi Yamada ₁ , Takashi Shin ₁ , Yuki Sawada ₁ , Hidenori Azami ₁ , Tomohiro Yamada ₁ , Takeyuki Nagashima ₁ , Kei Ohnuki ₁

Affiliation

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular metabolism. AMP or adenosine diphosphate (ADP) levels rise during metabolic stress, such as during nutrient starvation, hypoxia and muscle contraction, and bind to AMPK to induce activity. Recently, activation of AMPK has been considered an attractive therapeutic strategy in the field of human oncology. Structural optimization of lead compound 2, a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improved aqueous solubility, metabolic stability and animal pharmacokinetics (PK) and culminated in the identification of (5-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1H-benzimidazol-2-yl)(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)methanone ditosylate, ASP4132 (28). Studies on ASP4132 had advanced to clinical trials for the treatment of cancer.

中文翻译：

开发一种有效的，口服活性的腺苷单磷酸激活蛋白激酶（AMPK）激活剂ASP4132，作为治疗人类癌症的临床候选药物。

单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）在维持细胞代谢中起关键作用。AMP或二磷酸腺苷（ADP）的水平在代谢应激期间（例如在营养缺乏，缺氧和肌肉收缩过程中）升高，并与AMPK结合以诱导活性。近来，AMPK的激活已被认为是人类肿瘤学领域中有吸引力的治疗策略。铅化合物2的结构优化，一种新型AMPK活化剂，具有强大的AMPK活化活性和对人类癌细胞的有吸引力的选择性生长抑制作用，改善了水溶性，代谢稳定性和动物药代动力学（PK），最终鉴定为（5- { 1-[（（6-甲氧基吡啶-3-基）甲基]哌啶-4-基} -1H-苯并咪唑-2-基）（4-{[4-（三氟甲基）苯基]甲基}哌嗪-1-基）甲酮二甲苯磺酸盐，ASP4132（28）。ASP4132的研究已经发展到用于治疗癌症的临床试验。

更新日期：2020-01-09

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