Higley C A, Wilde R G, Maduskuie T P, Johnson A L, Pennev P, Billheimer J T, Robinson C S, Gillies P J, Wexler R R
DuPont Merck Research Laboratories, Wilmington, Delaware 19880-0402.
J Med Chem. 1994 Oct 14;37(21):3511-22. doi: 10.1021/jm00047a009.
A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.
已合成了一系列4,5-二芳基-2-(取代硫基)-1H-咪唑，并证明它们是酰基辅酶A：胆固醇酰基转移酶（ACAT）的有效抑制剂。本文报道了该系列化合物的设计、合成及构效关系。该系列中的一种化合物，N'-(2,4-二氟苯基)-N-[5-[(4,5-二芳基-1H-咪唑-2-基)硫基]戊基]-N-庚基脲（DuP 128），被选作肠道活性ACAT抑制剂进行开发。DuP 128在体外和体内均为有效的ACAT抑制剂，在大鼠肝微粒体中抑制ACAT的IC50 = 10 nM，且在体内具有强效的抗高胆固醇活性。
