Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

使用基于结构的设计技术鉴定了有效的，含1 H-吡唑并[3,4- b ]吡啶的人烟酰胺磷酸核糖基转移酶（NAMPT）酶的抑制剂。这些化合物中的许多在体外细胞培养实验中均显示出对人肿瘤细胞系的纳摩尔抗增殖活性，并且代表性实例（化合物26）在源自A2780细胞系的小鼠异种移植肿瘤模型中显示出令人鼓舞的体内功效。相对于先前研究的含咪唑并吡啶的NAMPT抑制剂，该分子还表现出减少的大鼠视网膜暴露。令人惊讶的是，化合物26尽管它是衍生自这些物种的NAMPT酶的有效抑制剂，但它在体外对小鼠和猴肿瘤细胞系的活性均较弱。该化合物对小鼠体内NAD的含量也仅表现出最小的影响，并且这些变化远不如含咪唑并吡啶的NAMPT抑制剂所产生的变化大。还获得了与NAMPT复合的化合物26的晶体结构和相应的PRPP衍生的核糖加合物。