Aldose Reductase Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4369
(23) Mu¨ller, P.; Hockwin, O.; Ohrloff, C. Comparison of Aldose
Reductase Inhibitors by Determination of IC50 with Bovine and
Rat Lens Extracts. Ophthalmic Res., 1985, 17, 115-119.
(24) Hockwin, O.; Mu¨ller, P.; Krolczyk, J .; McCue, B. A.; Mayer, P.
R. Determination of AL01576 Concentration In Rat Lenses and
Plasma by Bioassay for Aldose Reductase Activity Measure-
ments. Ophthalmic Res. 1989, 21, 285-291.
(25) Lindstad, R. I.; Hermansen, L. F.; McKinley-McKee, J . S.
Inhibition and Activation Studies on Sheep Liver Sorbitol
Dehydrogenase. Eur. J . Biochem. 1994, 221, 847-854.
(26) Ward, W. H. J .; Sennitt, C. M.; Ross, H.; Dingle, A.; Timmus,
D.; Mirrless, D. J .; Tuffin, D. P. Ponalrestat, a Potent and
Specific Inhibitor of Aldose Reductase. Biochem. Pharmacol.
1990, 39, 337-346.
(27) Fitzgerald, G. B.; Bauman, C.; Sajjat Hussoin, Md.; Wick, M.
M. 2,4-Dihydroxy benzylamine: A Specific Inhibitor of Glu-
tathione Reductase. Biochem. Pharmacol. 1991, 41, 185-190.
(28) Hu, T.; Merola, L. O.; Kuwabara, T.; Kinoshita, J . H. Prevention
and Reversal of Galactose Cataract in Rats with Topical Sorbinil.
Invest. Ophthalmol. Visual Sci. 1984, 25, 603-605.
(29) Sestanj, K.; Bellini, F.; Fung, S.; Abraham, N.; Treasurywala,
A.; Humber, L.; Simard-Duquesne, N.; Dvornik, D. N-[5-(Trifluoro-
methyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methyl-
glycine (Tolrestat), a Potent, Orally Active Aldose Reductase
Inhibitor. J . Med. Chem. 1984, 27, 255-256.
(30) Banditelli, S.; Boldrini, E.; Vilardo, G. P.; Cecconi, I.; Cappiello,
M.; Dal Monte, M.; Marini, I.; Del Corso, A.; Mura, U. A New
Approach Against Sugar Cataract Through Aldose Reductase
Inhibitors Exp. Eye Res. 1999, 69, 533-538.
(31) Chaudhry, P. S.; Cabrera, J .; J uliani, H. R.; Varma, S. D.
Inhibition of Human Lens Aldose Reductase by Flavonoids,
Sulindac and Indomethacin. Biochem. Pharmacol. 1983, 32,
1995-1998.
(32) Camber, O.; Edman, P. Factors Influencing the Corneal Perme-
ability of Prostaglandin F2R and Its Isopropyl Ester in Vitro. Int.
J . Pharm. 1987, 37, 27-32.
(33) Suhonen, P.; J a¨rvinen, T.; Peura, P.; Urtti, A. Permeability of
Pilocarpic Acid Diesters Across Albino Rabbit Cornea in Vitro.
Int. J . Pharm. 1991, 74, 221-228.
(34) Chien, D.-S.; Tang-Liu, D. D.-S.; Woodward, D. F. Ocular
Penetration and Bioconversion of Prostaglandin F2R Prodrugs
in Rabbit Cornea and Conjunctiva. J . Pharm. Sci. 1997, 86,
1180-1186.
(35) Bernstein, F. C.; Koetzle, T. F.; Williams, G. J . B.; Meyer, E. F.,
J r.; Brice, M. D.; Rodgers, J . R.; Kennard, O.; Shimanouchi, T.;
Tasumi, T. The Protein Data Bank: A Computer Based Archival
File for Macromolecular Structures. J . Mol. Biol. 1977, 112,
535-542.
(36) Wilson, D. K.; Bohren, K. M.; Gabbay, K. H.; Quiocho, F. A. An
Unlikely Sugar Substrate Site in the 1.65 Å Structure of the
Human Aldose Reductase Holoenzyme Implicated in Diabetic
Complications. Science 1992, 257, 81-84.
(37) Pearlman, D. A.; Case, D. A.; Caldwell, J . W.; Ross, W. S.;
Cheatham, T. E., III; Debolt, S.; Ferguson, D. M.; Seibel, G. L.;
Kollman, P. A. AMBER, a Package of Computer Programs for
Applying Molecular Mechanics, Normal Mode Analysis, Molec-
ular Dynamics and Free Energy Calculations To Simulate the
Structural and Energetic Properties of Molecules. Comput. Phys.
Commun. 1995, 91, 1-41.
(38) Pearlman, D. A.; Case, D. A.; Caldwell, J . W.; Ross, W. S.;
Cheatham, T. E., III; Ferguson, D. M.; Seibel, G.; Singh, U. C.;
Weiner, P. K.; Kollman, P. A. AMBER, version 4.1; Department
of Pharmaceutical Chemistry, University of California: San
Francisco, CA, 1995.
(39) Database searching (SWISS-PROT), sequence alignment, and
analysis of rat and human ALR2 sequences were carried out
using FASTA (Pearson, W. R. Proc. Natl. Acad. Sci. U.S.A. 1988,
85, 2444-2448) and BLAST programs (Pak, Y.; Wang, S. J . Phys.
Chem. B 2000, 104, 354-359). The SWISS-PROT accession
numbers for rat and human ALR2 types are P07943 and P15121,
respectively.
(42) Shoichet, B. K.; Bodian, D. L.; Kuntz, I. D. Molecular Modeling
Using Shape Descriptors. J . Comput. Chem. 1992, 13, 380-397.
(43) Connolly, M.; Gschwend, D. A.; Good, A. C.; Oshiro, C.; Kuntz,
I. D. DOCK, version 3.5; Department of Pharmaceutical Chem-
istry University of California: San Francisco, CA, 1995.
(44) Iemura, R.; Kawashima, T.; Fukuda, T., Ito, K.; Tsukamoto, G.
Synthesis of 2-(4-Substituted-1-piperazinyl)benzimidazoles
as H1-Antihistaminic Agents. J . Med. Chem. 1986, 29, 1178-
1183.
(45) Caroti, P.; Ceccotti, C.; Da Settimo, F.; Primofiore, G.; Franzone,
J . S.; Reboani, M. C.; Cravanzola, C. Synthesis, Antilipidemic
and Platelet Antiaggregatory Activity of 2-Aminobenzimidazole
Amide Derivatives. Farmaco 1989, 44, 227-255.
(46) Anaya de Parrodi, C.; Quintero-Cortes, L.; Sandoval-Ramirez,
J . A Short Synthesis of Astemizole. Synth. Commun. 1996, 26,
3323-3330.
(47) Hayman, S.; Kinoshita, J . H. Isolation and Properties of Lens
Aldose Reductase. J . Biol. Chem. 1965, 240, 877-882.
(48) SYBYL Molecular Modelling System, version 6.2; Tripos Inc.:
St. Louis, MO, 1998.
(49) Ferrin, T. E.; Huang, C. C.; J arvis, L. E.; Langridge, R. The
MIDAS Display System. J . Mol. Graphics 1998, 6, 13-27.
(50) Vinter, J . G.; Davis, A.; Saunders, M. R. Strategic Approaches
to Drug Design. 1. An Integrated Software Framework for
Molecular Modelling. J . Comput. Aided Mol. Des. 1987, 1, 31-
55.
(51) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
AM1: A New General Purpose Mechanical Molecular Model. J .
Am. Chem. Soc. 1985, 107, 3902-3909.
(52) MOPAC (version 6.0) is available from Quantum Chemistry
Program Exchange, No. 455.
(53) Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz,
K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell,
J . W.; Kollman, P. A. A Second Generation Force Field for the
Simulation of Proteins, Nucleic Acids, and Organic Molecules.
J . Am. Chem. Soc. 1995, 117, 5179-5197.
(54) Rastelli, G.; Costantino, L. Molecular Dynamics Simulations of
the Structure of Aldose Reductase Complexed with the Inhibitor
Tolrestat. Bioorg. Med. Chem. Lett. 1998, 8, 641-646.
(55) Bohren, K. M.; Grimshaw, C. E.; Lai, C. J .; Harrison, D. H.;
Ringe, D.; Petsko, G. A.; Gabbay, K. H. Tyrosine-48 is the
Proton Donor and Histidine-110 Directs Substrate Stereo-
chemical Selectivity in the Reduction Reaction of Human
Aldose Reductase: Enzyme Kinetics and Crystal Structure
of the Y48H Mutant Enzyme. Biochemistry 1994, 33, 2021-
2032.
(56) Petrash, J . M.; Hodoshek, M.; Brooks, B. R.; Kador, P. F.
Catalytic Mechanism of Aldose Reductase Studied by the
Combined Potentials of Quantum Mechanics and Molecular
Mechanics. Biophys. Chem. 1998, 70, 203-216.
(57) Ehrig, T.; Bohren, K. M.; Prendergast, F. G.; Gabbay, K. H.
Mechanism of Aldose Reductase Inhibition: Binding of NADP+/
NADPH and Alrestatin-like Inhibitors. Biochemistry 1994, 33,
7157-7165.
(58) De Winter, H. L.; von Itzstein, M. Aldose Reductase as a Target
for Drug Design: Molecular Modeling Calculations on the
Binding of Acyclic Sugar Substrates to the Enzyme. Biochemistry
1995, 34, 8299-8308.
(59) Singh, U. C.; Kollmann, P. A. An Approach to Computing
Electrostatic Charges for Molecules. J . Comput. Chem. 1984, 5,
129-144.
(60) Head, J .; Zerner, M. C. A Broyden-Fletcher-Goldfarb-Shanno
Optimization Procedure for Molecular Geometries. Chem. Phys.
Lett. 1985, 122, 264-274.
(61) Connolly, M. L. Solvent-Accessible Surfaces of Proteins and
Nucleic Acids. Science 1983, 221, 709-713.
(62) Connolly, M. L. Analytical Molecular Surface Calculation. J .
Appl. Crystallogr. 1983, 16, 548-558.
(63) J orgensen, W. L.; Chandrasekhar, J .; Madura, J . D.; Impey,
R. W.; Klein, M. L. Comparison of Simple Potential Functions
for Simulating Liquid Water. J . Chem. Phys. 1983, 79, 926-
935.
(40) Meng, E. C.; Shoichet, B. K.; Kuntz, I. D. Automated Docking
with Grid-Based Energy Evaluation. J . Comput. Chem. 1992,
13, 505-524.
(41) Meng, E. C.; Gschwend, D. A.; Blaney, J . M.; Kuntz, I. D.
Orientational Sampling and Rigid-Body Minimization in
Molecular Docking. Proteins: Struct., Funct., Genet. 1993, 17,
266-278.
(64) Berendsen, H. J . C.; Postma, J . P. M.; van Gunsteren, W. F.;
DiNola, A.; Haak, J . R. Molecular Dynamics with Coupling to
an External Bath. J . Chem. Phys. 1984, 81, 3684-3690.
J M0109210