(R)-ND-336—designated as compound (R)-5—is a highly selective inhibitor of matrix metalloproteinase (MMP)-9 with efficacy in accelerating diabetic wound healing in murine models. (R)-ND-336 belongs to the class of thiirane inhibitors of MMPs and it is currently undergoing Investigation New Drug (IND)-enabling studies. We investigated the in vitro metabolism of (R)-ND-336 using S9 fractions obtained from mice, rats, dogs, minipigs, monkeys, and humans in order to select the rodent and nonrodent species for toxicology studies. Three metabolites were observed. One metabolite, M3, was observed across all species. Metabolite M2 was found in rats, monkeys, and humans. Metabolite M1 was observed only in rats. The identities of the metabolites were suggested by liquid chromatography/tandem mass spectroscopy (LC/MS-MS) analyses, which were authenticated by comparison to synthetic samples. Metabolites M2 and M3 arise from oxidative deamination of (R)-ND-336 by monoamine oxidase to give the arylaldehyde as a transient (and unobserved) intermediate. Reductive metabolism of this aldehyde gives the alcohol metabolite M2, while further oxidative metabolism of the aldehyde produces the carboxylate metabolite M3. A minor route of metabolism, seen only in rats, is N-acetylation of (R)-ND-336 to give the acetamide M1. The metabolism of (R)-ND-336 is distinctly different from that of the prototype member of this thiirane class ((±)-1, lacking the 4-aminomethyl aryl substituent) which is metabolized primarily by oxidation α to the sulfone to lead to a benzenesulfinate metabolite. All three metabolites are poorer MMP-9 inhibitors, compared to (R)-ND-336 (MMP-9, K_i = 19 nM): M3, MMP-9 IC₅₀ > 100 μM; M2, K_i = 390 nM; and M1, IC₅₀ > 100 μM). The rat and the minipig were selected as the rodent and nonrodent species, respectively, for toxicology studies.

中文翻译：

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选择性基质金属蛋白酶 9 抑制剂 (R)-ND-336 的代谢

( R )-ND-336 - 指定为化合物 ( R ) -5 - 是一种高选择性的基质金属蛋白酶 (MMP)-9 抑制剂，在小鼠模型中具有加速糖尿病伤口愈合的功效。( R )-ND-336 属于 MMP 的硫杂丙环类抑制剂，目前正在进行新药 (IND) 研究。我们使用从小鼠、大鼠、狗、小型猪、猴子和人类获得的 S9 组分研究了 ( R )-ND-336的体外代谢，以便选择啮齿动物和非啮齿动物进行毒理学研究。观察到三种代谢物。在所有物种中都观察到一种代谢物M3 。代谢物M2在大鼠、猴子和人类中发现。仅在大鼠中观察到代谢物M1 。通过液相色谱/串联质谱 (LC/MS-MS) 分析表明代谢物的特性，并通过与合成样品的比较进行验证。代谢物M2和M3来自 ( R )-ND-336 通过单胺氧化酶的氧化脱氨作用，得到芳醛作为一种瞬时（和未观察到的）中间体。该醛的还原代谢产生醇代谢物M2，而醛的进一步氧化代谢产生羧酸代谢物M3。仅在大鼠中可见的次要代谢途径是（R )-ND-336 得到乙酰胺M1。( R )-ND-336 的代谢明显不同于该硫杂环丙烷类的原型成员 ((±) -1，缺乏 4-氨基甲基芳基取代基)，后者主要通过氧化 α 代谢为砜以导致为苯亚磺酸盐代谢物。与 ( R )-ND-336 (MMP-9, K _i = 19 nM)相比，所有三种代谢物都是较差的 MMP-9 抑制剂： M3，MMP-9 IC ₅₀ > 100 μM；M2 , K _i = 390 nM; 和M1 , IC ₅₀> 100 微米）。分别选择大鼠和小型猪作为啮齿动物和非啮齿动物进行毒理学研究。