Emerging from an HTS campaign, novel steroid-based histamine H₃ receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H₃ receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.

从HTS运动中涌现，鉴定并表征了新型的基于类固醇的组胺H ₃受体拮抗剂。结合命中化合物的结构部分以改善结合亲和力，从而产生化合物4作为前导分子。在由于二氨基类固醇衍生物的多用途修饰而导致的前导优化过程中，发现了几种对亚组胺H ₃受体具有亲和力的体外有效化合物。通过调节碱度，成功减少了与鼠毒蕈碱受体的不利结合。化合物20在大鼠成虫模型中显示出显着的体内活性，并且将来可以用作药理学工具。