Mahé Y F, Buan B, Bernard B A
Hair Biology Research Group, L'Oréal, Centre de Recherche C.Zviak, Clichy, France.
Skin Pharmacol. 1996;9(3):177-83. doi: 10.1159/000211413.
It has been previously reported that minoxidil inhibits the activity of lysyl hydroxylase (LH), an enzyme which catalyzes the formation of hydroxylysine, which is necessary for proper maturation of collagen at the transcriptional and enzymatic levels. Using the reverse transcriptase-polymerase chain reaction, we confirmed that this inhibition occurred at least at the transcriptional level. Furthermore, we took advantage of this sensitive and rapid method to perform a quantitative structure activity relation study using several compounds structurally related to minoxidil. We found that when the C6 of the pyrimidinyl moiety was substituted, it had to be by a tertiary nitrogen, i.e. an N-piperidin ring for the inhibition of LH mRNA synthesis to be observed. Surprisingly, however, we found that 2,4-diamino-pyrimidin-3-oxide, a new compound lacking an organic moiety para to the nitroxide oxygen, also retained a high inhibitory effect on LH mRNA expression, comparable to that of minoxidil. We thus conclude that the presence of a substituent para to the nitroxide oxygen is dispensable for inhibition of LH mRNA to be observed in vitro. This brings new insights into the design of therapeutic agents useful in any condition where an overproduction of mature collagen is unwanted, i.e. accelerated wound healing, keloids and localized scleroderma.
此前有报道称，米诺地尔可抑制赖氨酰羟化酶（LH）的活性，该酶催化羟赖氨酸的形成，而羟赖氨酸在转录和酶促水平上对胶原蛋白的正常成熟是必需的。我们使用逆转录聚合酶链反应证实，这种抑制至少发生在转录水平。此外，我们利用这种灵敏且快速的方法，使用几种与米诺地尔结构相关的化合物进行了定量构效关系研究。我们发现，当嘧啶基部分的C6被取代时，必须被叔氮取代，即N-哌啶环，才能观察到对LH mRNA合成的抑制。然而，令人惊讶的是，我们发现2,4-二氨基嘧啶-3-氧化物，一种在硝基氧对位缺少有机部分的新化合物，对LH mRNA表达也保留了高抑制作用，与米诺地尔相当。因此，我们得出结论，在体外观察到对LH mRNA的抑制时，硝基氧对位存在取代基并非必需。这为设计用于任何不需要成熟胶原蛋白过度产生的情况，即加速伤口愈合、瘢痕疙瘩和局限性硬皮病的治疗药物带来了新的见解。
