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2.
Bioorg Med Chem Lett ; 11(2): 243-6, 2001 Jan 22.
Article in English | MEDLINE | ID: mdl-11206469

ABSTRACT

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.


Subject(s)
Lactams/pharmacokinetics , Leukocyte Elastase/antagonists & inhibitors , Neutrophils/drug effects , Acylation , Administration, Oral , Animals , Binding Sites , Cricetinae , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Lactams/chemistry , Lactams/pharmacology , Models, Molecular , Neutrophils/enzymology , Pancreas/enzymology , Protein Binding , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Solubility , Structure-Activity Relationship , Swine
3.
J Med Chem ; 36(23): 3646-57, 1993 Nov 12.
Article in English | MEDLINE | ID: mdl-8246233

ABSTRACT

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.


Subject(s)
Cholesterol/biosynthesis , Heptanoates/chemical synthesis , Hydroxy Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Imidazoles/chemical synthesis , Animals , Crystallography, X-Ray , Heptanoates/pharmacology , Hydroxy Acids/pharmacology , Imidazoles/pharmacology , Lovastatin/pharmacology , Microsomes, Liver/enzymology , Molecular Structure , Pravastatin/pharmacology , Rats
4.
J Med Chem ; 36(23): 3658-62, 1993 Nov 12.
Article in English | MEDLINE | ID: mdl-8246234

ABSTRACT

A series of 7-[2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl]-3,5- dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin.


Subject(s)
Cholesterol/biosynthesis , Hydroxy Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Pyrroles/chemical synthesis , Carcinoma, Hepatocellular/metabolism , Humans , Hydroxy Acids/pharmacology , Liver Neoplasms/metabolism , Lovastatin/pharmacology , Molecular Structure , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
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