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12 results on '"Beno, B. R."'

6. Conformationally Restricted Homotryptamines. 2. Indole Cyclopropylmethylamines as Selective Serotonin Reuptake Inhibitors

Author

Mattson, R. J., Catt, J. D., Denhart, D. J., Deskus, J. A., Ditta, J. L., Higgins, M. A., Marcin, L. R., Sloan, C. P., Beno, B. R., Gao, Q., Cunningham, M. A., Mattson, G. K., Molski, T. F., Taber, M. T., and Lodge, N. J.

Abstract

A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.

Published
2005

7. Stereoselective Synthesis of New Conformationally Restricted Analogues of a Potent CGRP Receptor Antagonist

Author

Zuev, D., Michne, J. A., Huang, H., Beno, B. R., Wu, D., Gao, Q., Torrente, J. R., Xu, C., Conway, C. M., Macor, J. E., and Dubowchik, G. M.

Abstract

A stereocontrolled racemic synthesis of conformationally restricted analogues 2a and 2b of a potent CGRP receptor antagonist 1 by novel functionalization of 2-substituted octahydropyrido[1,2-a]pyrazin-6-ones is described. The new diastereoselective LDA-promoted α-nitration of intermediate lactams established the required trans-configuration in the desired products.

Published
2005

11. Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints: simultaneous optimization and structure-based diversity.

Author

Mason JS and Beno BR

Subjects
Binding Sites, Computer Graphics, Computer Simulation, Factor Xa Inhibitors, Indicators and Reagents, Models, Molecular, Protein Binding, Combinatorial Chemistry Techniques, Drug Design, Models, Chemical
Abstract

New applications of fingerprints of multiple potential 4-point three-dimensional (3D) pharmacophores in combinatorial library design and virtual screening are presented. Preliminary results demonstrating the feasibility of a simulated annealing process for combinatorial reagent selection that concurrently optimizes product diversity in BCUT chemistry space and in terms of unique 4-point pharmacophores are discussed, and the advantage of using a customized chemistry-space derived for the library design is demonstrated. In addition, an extension to the multiple pharmacophore method for structure-based design that uses the shape of the target site as an additional constraint is presented. This development enables the docking process to be quantified in terms of the number and identities of the pharmacophoric hypotheses that can be matched by a compound or a library of compounds. The design of an example combinatorial library based on the Ugi condensation reaction and a serine protease active site is described.

Published
2000
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12. An antibody exo Diels-Alderase inhibitor complex at 1.95 angstrom resolution.

Author

Heine A, Stura EA, Yli-Kauhaluoma JT, Gao C, Deng Q, Beno BR, Houk KN, Janda KD, and Wilson IA

Subjects
Antibodies, Catalytic immunology, Antibodies, Catalytic metabolism, Catalysis, Chemistry, Organic, Crystallography, X-Ray, Ferrous Compounds immunology, Ferrous Compounds metabolism, Haptens chemistry, Haptens immunology, Hydrogen Bonding, Hydrogen-Ion Concentration, Immunoglobulin Fab Fragments chemistry, Metallocenes, Models, Molecular, Organic Chemistry Phenomena, Stereoisomerism, Thermodynamics, Antibodies, Catalytic chemistry, Ferrous Compounds chemistry
Abstract

A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system. The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess. The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control. Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid-H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate. This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity. Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exo stereoisomer is the preferred product.

Published
1998
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