Brown G R, Hollinshead D M, Stokes E S, Clarke D S, Eakin M A, Foubister A J, Glossop S C, Griffiths D, Johnson M C, McTaggart F, Mirrlees D J, Smith G J, Wood R
Cardiovascular Metabolism & Muscoskeletal Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
J Med Chem. 1999 Apr 8;42(7):1306-11. doi: 10.1021/jm990038q.
Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.
报道了新型的3-取代奎宁环胆固醇生物合成抑制剂。这些化合物是针对体内氧化角鲨烯环化酶-羊毛甾醇合酶（OSC）抑制进行优化的，而非基于体外OSC抑制通过传统的构效关系信息优化。因此，对口服给药大鼠的HPLC脂质谱进行检测，以显示胆固醇生物合成中间体以及胆固醇水平是否降低。迅速发现了一种新的取代奎宁环药效团18a - c用于抑制OSC，并且通过确认有效的OSC抑制作用对最有前景的抑制剂进行了验证。化合物16对人给出的IC50值为83±11 nM，对大鼠的IC50值为124±14 nM，同时具有口服和对源自OSC抑制的胆固醇生物合成的选择性抑制作用（大鼠，ED50 = 1.3±0.7 mg/kg，n = 5；狨猴，15 mg/kg剂量，n = 3，导致完全抑制）。这些3-取代奎宁环衍生自先前已知在角鲨烯合酶步骤抑制胆固醇生物合成的奎宁环系列，可能提供一系列通过抑制OSC起作用的新型降胆固醇药物。
