title: Rational design, synthesis, and potency of N-substituted indoles, pyrroles, and triarylpyrazoles as potential fructose 1,6-bisphosphatase inhibitors.
abstract: By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole-, indole-, and pyrazole-based compounds were evaluated as potential fructose 1,6-bisphosphatase (FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1-[4-(trifluoromethyl)benzoyl]-1H-indole-5-carboxamide, 1-(alpha-naphthalen-1-ylsulfonyl)-7-nitro-1H-indole, 5-(4-carboxyphenyl)-3-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole, 1-(4-carboxyphenylsulfonyl)-1H-pyrrole, and 1-(4-carbomethoxyphenylsulfonyl)-1H-pyrrole were synthesized and tested for inhibition of FBPase. The IC(50) values were determined to be 0.991 and 1.34 microM, and 575, 135, and 32 nM, respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 microM) by an order of magnitude; indeed, the best inhibitor showed an IC(50) value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.
authors.affiliation: Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA 02125, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rudnitskaya
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Borkin
authors.forename: Ken
authors.initials: K
authors.lastname: Huynh
authors.forename: Béla
authors.initials: B
authors.lastname: Török
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stieglitz
mesh_terms: D000818:Animals; D001665:Binding Sites; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007211:Indoles; D011720:Pyrazoles; D011758:Pyrroles; D006597:Fructose-Bisphosphatase