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A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N'-tetrazole or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL cholesterol 113% in rats with pre-established hypercholesterolemia.

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Using photoaffinity labeling, we have identified a region in mammalian farnesyl-protein transferase (FPTase) involved in substrate recognition. The photolabel used (Compound 1) is a peptide containing the photoactive amino acid p-benzoylphenylalanine (Bpa). Upon exposure to UV light. Compound 1 inhibits FPTase activity in a time- and concentration-dependent manner. Photoinhibition of FPTase activity by Compound 1 is prevented by adding H-Ras to the reaction mixture, indicating that labeling is targeted to the enzyme active site. We used peptide mapping by HPLC, Edman sequencing, and matrix-assisted time-of-flight (MALDI-TOF) mass spectrometry to identify the site of interaction with radiolabeled Compound 1. These experiments indicate that a specific region of the alpha subunit of the enzyme, Asp110-Arg112, is involved in substrate binding and suggest that Glu111 is likely to be the residue covalently modified by the photoaffinity label. Sequence alignments between yeast and mammalian FPTases reveal that Glu111 is conserved. The implications of this finding are discussed in light of previous mutagenesis studies on FPTase.