Duan James J-W, Jiang Bin, Lu Zhonghui, Stachura Sylwia, Weigelt Carolyn A, Sack John S, Khan Javed, Ruzanov Max, Wu Dauh-Rurng, Yarde Melissa, Shen Ding-Ren, Zhao Qihong, Salter-Cid Luisa M, Carter Percy H, Murali Dhar T G
Research and Early Development, Bristol Myers Squibb Company, Princeton, NJ 08543-4000, United States.
Research and Early Development, Bristol Myers Squibb Company, Princeton, NJ 08543-4000, United States.
Bioorg Med Chem Lett. 2020 Oct 1;30(19):127441. doi: 10.1016/j.bmcl.2020.127441. Epub 2020 Jul 29.
In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC 11 nM) that are highly selective against PXR, LXRα and LXRβ. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.
为了发现用于治疗炎症性疾病的RORγt口服反向激动剂，人们发现了一个新的2,6 - 二氟苄基醚系列的环戊基砜，其活性出人意料地比相应的醇衍生物更强。当与更优化的苯基（(R)-3 - 苯基吡咯烷 - 3 - 基）砜模板结合时，2,6 - 二氟苄基醚产生了一组非常有效的RORγt反向激动剂（例如化合物26，RORγt Gal4 EC为11 nM），它们对PXR、LXRα和LXRβ具有高度选择性。在优化了在人和小鼠肝微粒体中的稳定性后，对化合物29和38进行了体内评估，发现它们在小鼠体内具有良好的口服生物利用度（分别为56%和101%）。化合物27与RORγt的X射线共晶体结构表明，庞大的苄基醚基团导致蛋白质的11号螺旋部分展开，形成一个新的、扩大的结合位点，该位点很好地容纳了苄基醚部分，从而带来净活性增益。
