A MINOXIDIL-RELATED COMPOUND LACKING A C6 SUBSTITUTION STILL EXHIBITSSTRONG ANTI-LYSYL HYDROXYLASE-ACTIVITY IN-VITRO

It has been previously reported that minoxidil inhibits the activity o f lysyl hydroxylase (LH), an enzyme which catalyzes the formation of h ydroxylysine, which is necessary for proper maturation of collagen at the transcriptional and enzymatic levels. Using the reverse transcript ase-polymerase chain reaction, we confirmed that this inhibition occur red at least at the transcriptional level. Furthermore, we took advant age of this sensitive and rapid method to perform a quantitative struc ture activity relation study using several compounds structurally rela ted 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-piperi din ring for the inhibition of LH mRNA synthesis to be observed. Surpr isingly, however, we found that 2,4-diamino-pyrimidin-3-oxide, a new c ompound lacking an organic moiety para to the nitroxide oxygen, also r etained 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 a nd localized scleroderma.