1,4-Diaryl-azetidin-2-ones
 John W. Clader et al (J. Med. Chem. 1996, 39, 3684-3693) reported a series of azetidinone cholesterol absorption inhibitors related to compound 2(6 in paper). They focused on detailed structure-activity relationship of azetidinone compounds to probe the effect and sensitivity of the nature and pattern of substitution on the hypocholesterolemic activity in 7-day cholesterol-fed hamster model. Investigation identified that 4-alkoxyphenyl and absolute stereochemistry at C-4 (compound 23), well placed phenylalkyl group (compound 105) and monosubstitution at C-3, an aryl group at N-1 irrespective of substitutions (compound 65) and azetidinone scaffolds is essential for the in vivo CAI activity. Compound 23 Compound 105 Compound 65 Compound 6
X- 4-C2H5O X- OCH3 R- H X- 4-CH3O
R1- Ph(CH2)3 Y- H R1- Ph(CH2)3
R2- H R1- F R2- Ph(CH2)3 R2- H
SC- -52%(50mg/kg/day) -30%(50mg/kg/day) -49%(50mg/kg/day) -29% (50mg/kg/day)
LCE- -98%(50mg/kg/day) -94% (20mg/kg/day) -95%(40mg/kg/day) -77.5%(50mg/kg/day)

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Rosenblum et al (J. Med. Chem. 1998, 41, 973-980) designed and synthesized a series of analogues of compound 2 in which hydroxyl groups and fluorine atoms are strategically placed to study the SAR of 2-azetidinone cholesterol absorption inhibitors. In a 7-day cholesterol-fed hamster model used for the CAI activity, Compound 1 showed excellent activity with LCE ED50 of 0.04 mg/kg/day, a 50-fold increase in potency as compared to 2. Significant improvements in CAI activity relative to 2 were observed in the majority of analogues in which strategic substitutions were incorporated on phenyl rings at N-1, C-4 and C-3 side chain of azetidinone such as p- fluorine substitution on phenyl rings at N-1 and C-3 side chain (compound 20), 4-alkoxy groups on phenyl rings at C-4 (compound 20), 3-acetoxy substitution on C-3 side chain (compound 26) and 3’S-hydroxyl substituent at C-3 side chain (compound