LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave., Waltham, MA 02451, USA.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4044-7. doi: 10.1016/j.bmcl.2013.05.068. Epub 2013 May 30.
This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.
这封信描述了一种强效且高选择性组胺 H3 受体 (H3R) 拮抗剂 5-氟-2-甲基-N-[2-甲基-4-(2-甲基[1,3']联吡啶基-1'-基)苯基]苯甲酰胺 (1) 的四个立体异构体 (8a-8d) 的不对称合成。测定了 8a-8d 的物理化学性质、体外 H3R 亲和力和 ADME。立体异构体 8c(2S,3'S) 在体外 H3R 亲和力方面优于其他三个立体异构体，并被选中用于进一步研究体内 PK 和药物安全性。化合物 8c 表现出优异的 PK 特性，具有高暴露量、理想的脑血浆比和合理的脑半衰期。然而，所有立体异构体均表现出相似的不期望的 hERG 亲和力。
