Inhibitors of cholesterol biosynthesis. 1. 3,5-Dihydroxy-7-(N-imidazolyl)-6-heptenoates and -heptanoates, a novel series of HMG-CoA reductase inhibitors.

3,5-Dihydroxy-7-(N-imidazolyl)heptanoates 4 and the corresponding heptenoates 5 were synthesized as novel classes of potent HMG-CoA reductase (HMGR) inhibitors in which members of the latter series possess enzyme inhibitory activity greater than that of lovastatin 1 and pravastatin 2. Structure-activity studies show that the 7-(N-imidazolyl)heptenoates 5 are more active than the corresponding heptanoates 4. For both imidazolyl series, the 4-fluorophenyl group is preferred at C-5, and a broad range of aryl substituents which promote widely different lipophilicities is tolerated at C-4. While the CF3 group is preferred at C-2 in the heptanoate series, the 2-(1-methylethyl) substituent is optimal in the heptenoate series. The 2-(1-methylethyl) and 5-(4-fluorophenyl) groups can be interchanged in the latter series as exemplified by 5ab. Enzyme inhibitory activity resides principally in the 3R,5S series. These potent HMGR inhibitory activities by members of the heptenoate series translated well into whole cell activities in HepG2 cells. X-ray crystallographic studies on the active enantiomer 28 reveal noncoplanarity of the heptenoate C-C double bond with the imidazole ring; this finding provides an explanation for the high acid stability of the heptenoate series.

Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines.

A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.