Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3873-8. doi: 10.1016/j.bmcl.2012.04.117. Epub 2012 May 2.
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
从恶二唑酰胺高通量筛选 (HTS) 命中物中发现了一系列新型 DGAT-1 抑制剂。通过优化效力和配体脂溶性效率 (LLE)，得到了含有羧酸的临床候选物 53（AZD3988），其 DGAT-1 效力优异（0.6 nM），药代动力学特性良好，临床前体内疗效显著，可通过 PK/PD 关系进行合理化解释。
