Genentech Inc., South San Francisco, CA 94080, USA.
Charles River Laboratories, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2090-2093. doi: 10.1016/j.bmcl.2019.07.013. Epub 2019 Jul 6.
Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.
酚基团是导致雌激素受体 alpha（ERα）临床候选药物 GDC-0927 高清除率和低口服生物利用度的原因。为了寻找一种具有改善药代动力学（PK）性质的备用分子，进行了详尽的搜索，虽然这通常是以所需的效力和降解效率为代价的。C-8 羟基色烯 30 是第一个含有酚基团的色烯的例子，它不仅保持了优异的效力，而且在大鼠中还表现出了 10 倍更高的口服暴露。推测大鼠体内清除率的提高是由于 C-8 羟基基团受到空间位阻保护，避免与葡萄糖醛酸结合。优异的效力强调了在色烯核心的 C-6 或 C-7 取代假定不可缺少的酚基团的可能性。获得共晶结构以突出关键相互作用的变化，并使保留的效力合理化。
