Ali S M, Tedford C E, Gregory R, Handley M K, Yates S L, Hirth W W, Phillips J G
Gliatech Inc., 23420 Commerce Park Road, Cleveland, Ohio 44122, USA.
J Med Chem. 1999 Mar 11;42(5):903-9. doi: 10.1021/jm980310g.
New, potent, and selective histamine H3 receptor antagonists have been synthesized by employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss operational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas 26-31 are analogues prepared by incorporation of the trans-(+/-)-cyclopropane at the C-4 position of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S, 2S)-cyclopropyl enantiomers of the most potent racemic compound 31 (Ki = 0.33 +/- 0.13 nM) demonstrated a stereopreference in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (Ki = 0.18 +/- 0.04 nM) versus the (1S,2S) enantiomer 33 (Ki = 5.3 +/- 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)imidazole (32) is one of the most potent histamine H3 receptor antagonists reported to date.
通过以下方式合成了新型、强效且具有选择性的组胺H3受体拮抗剂：（1）使用位置适当的非极性乙炔间隔基团；（2）在咪唑头基的C-4位置与乙炔间隔基团之间，采用二碳直链连接基团或构象受限的反式环丙烷环；（3）采用Topliss操作方案进行侧链取代以优化疏水区域。化合物9 - 18是用二碳直链连接基团合成的实例，而化合物26 - 31是通过在咪唑头基的C-4位置引入反式（+/-）-环丙烷制备的类似物。对最有效的外消旋化合物31（Ki = 0.33 +/- 0.13 nM）的（1R,2R）-和（1S, 2S）-环丙基对映体进行合成，结果表明在H3受体结合亲和力方面，（1R,2R）对映体32（Ki = 0.18 +/- 0.04 nM）相对于（1S,2S）对映体33（Ki = 5.3 +/- 0.5 nM）具有立体选择性。（1R,2R）-4-（2-（5,5-二甲基己-1-炔基）环丙基）咪唑（32）是迄今为止报道的最有效的组胺H3受体拮抗剂之一。
