Baldassarri Cecilia, Giorgioni Gianfabio, Piergentili Alessandro, Quaglia Wilma, Fontana Stefano, Mammoli Valerio, Minazzato Gabriele, Marangoni Elisa, Gasparrini Massimiliano, Sorci Leonardo, Raffaelli Nadia, Cappellacci Loredana, Petrelli Riccardo, Del Bello Fabio
Medicinal Chemistry Unit, School of Pharmacy, Chemistry Interdisciplinary Project (ChIP), University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy.
Center for Drug Discovery and Development-DMPK, Aptuit, an Evotec Company, Via A. Fleming 4, 37135 Verona, Italy.
Pharmaceuticals (Basel). 2023 Jan 27;16(2):189. doi: 10.3390/ph16020189.
The prevention of nicotinamide adenine dinucleotide (NAD) biosynthesis is considered an attractive therapeutic approach against cancer, considering that tumor cells are characterized by an increased need for NAD to fuel their reprogrammed metabolism. On the other hand, the decline of NAD is a hallmark of some pathological conditions, including neurodegeneration and metabolic diseases, and boosting NAD biosynthesis has proven to be of therapeutic relevance. Therefore, targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD biosynthesis from nicotinamide (NAM) and nicotinic acid (NA), respectively, is considered a promising strategy to modulate intracellular NAD pool. While potent NAMPT inhibitors and activators have been developed, the search for NAPRT modulators is still in its infancy. In this work, we report on the identification of a new class of NAPRT modulators bearing the 1,2-dimethylbenzimidazole scaffold properly substituted in position 5. In particular, compounds , , and emerged as the first NAPRT activators reported so far, while behaved as a noncompetitive inhibitor toward NA ( = 338 µM) and a mixed inhibitor toward phosphoribosyl pyrophosphate (PRPP) ( = 134 µM). From in vitro pharmacokinetic studies, compound showed an overall good ADME profile. To rationalize the obtained results, docking studies were performed on the NAPRT structure. Moreover, a preliminary pharmacophore model was built to shed light on the shift from inhibitors to activators.
鉴于肿瘤细胞的特征是对烟酰胺腺嘌呤二核苷酸（NAD）的需求增加，以维持其重编程代谢，因此预防NAD生物合成被认为是一种有吸引力的癌症治疗方法。另一方面，NAD水平下降是包括神经退行性变和代谢疾病在内的一些病理状况的标志，并且提高NAD生物合成已被证明具有治疗意义。因此，分别靶向调节从烟酰胺（NAM）和烟酸（NA）合成NAD的烟酰胺磷酸核糖基转移酶（NAMPT）和烟酸磷酸核糖基转移酶（NAPRT），被认为是调节细胞内NAD池的一种有前景的策略。虽然已经开发出了有效的NAMPT抑制剂和激活剂，但对NAPRT调节剂的研究仍处于起步阶段。在这项工作中，我们报告了一类新的带有在5位适当取代的1,2 - 二甲基苯并咪唑支架的NAPRT调节剂的鉴定。特别地，化合物 、 和 是迄今为止报道的首批NAPRT激活剂，而 对NA表现为非竞争性抑制剂（ = 338 µM），对磷酸核糖焦磷酸（PRPP）表现为混合型抑制剂（ = 134 µM）。从体外药代动力学研究来看，化合物 显示出总体良好的药代动力学性质。为了合理解释所获得的结果，对NAPRT结构进行了对接研究。此外，构建了一个初步的药效团模型，以阐明从抑制剂到激活剂的转变。
