Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePP_i), a potent mineralization inhibitor, to phosphate (P_i). By the controlled hydrolysis of ePP_i, TNAP maintains the correct ratio of P_i to ePP_i and therefore enables normal skeletal and dental calcification. In other areas of the body low ePP_i levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePP_i. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo.

组织非特异性碱性磷酸酶（TNAP）通过其将强力矿化抑制剂胞外无机焦磷酸盐（ePP _i）水解为磷酸盐（P _i）的能力，对骨基质矿化至关重要。通过ePP _i的受控水解，TNAP可以维持P _i与ePP _i的正确比率，因此可以实现正常的骨骼和牙齿钙化。在人体的其他部位，低ePP _i水平会导致病理性软组织钙化的发展，并可能发展为多种疾病。已显示TNAP抑制剂可通过增加ePP _i来阻止这些过程。在本文中，我们描述了使用全血分析来优化先前描述的一系列TNAP抑制剂，从而产生5-（（5-氯-2-甲氧基苯基）磺酰胺基）烟酰胺（SBI-425），这是一种有效，选择性和口服可生物利用的化合物在体内强有力地抑制TNAP 。