Trius Therapeutics, Inc.

Merck Sharp + Dohme Corp.

Takeda San Diego, Inc.

Mark Hilgers

Mark Stidham

John F Finn

John M Finn

Junhu Zhang

Xiaoming Li

Robert Haselbeck

Zhiyong Chen

Leslie William Tari

Thanh To Lam

Karen Joy Shaw

Michael Trzoss

Vickie L Brown-Driver

Christopher John Creighton

Kedar Gc

Robert J Skene

Daniel Bensen

Michael E Jung

Ellen Chi

Keith P Wilson

Mark Knuth

David J Hosfield

Ciaran N Cronin

Bi Ching Sang

Kathleen Aertgeerts

Hua Zou

Oleg Brodsky

Marc E Navre

Mark Cunningham

Lucy Aguirre Kohnen

Darbi Witmer

Les Tari

Novel gyrase inhibitors and related compositions and methods are useful for impeding bacterial growth. Compounds of Formula (I), are disclosed: Formula (I), wherein Y is N or CH; Z is N or CR; Ris H, a substituted or unsubstituted hydrocarbyl residue (1-3C) containing 0-2 heteroatoms selected from O, S and N, or is an inorganic residue; L is O, S, NR, or CRR; Ris H or Calkyl; Rand Rare each independently H or Calkyl; Ris H, a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue; Ris H, an inorganic residue, or a hydrocarbyl residue (1-30C) containing 0-12 heteroatoms selected from O, S and N and containing 0-10 inorganic residues, wherein Rand Rtogether may join to form a fused ring; and Ris selected from the group consisting of H, Calkyl, Calkenyl, Calkynyl, halo Calkyl, halo Calkenyl, halo Calkynyl, Chydroxyalkyl, Calkyl chloride, Calkenyl chloride, and Calkynyl chloride; or a pharmaceutically-acceptable salt, ester, or prodrug thereof. 

Gyrase inhibitors

Novel gyrase inhibitors and related compositions and methods are useful for impeding bacterial growth. Compounds of Formula I are disclosed: 

The present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R, Rand Z are as described herein. The disclosure also provides pharmaceutical compositions thereof; and methods for inhibiting DHFR activity; and methods for treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection by administering a compound of Formula I.

Dihydrofolate reductase inhibitors

The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a &#x3b2;-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

Identification and application of antibiotic synergy

The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.

Method for identifying drug-sensitizing antisense DNA fragments and use thereof

Provided are crystals relating to histone deacetylase 2 (HDAC-2) and its various uses.

Crystallization of histone deacetylase 2

Provided are crystals relating to 11-Beta-Hydroxysteroid Dehydrogenase type 1 and its various uses.

Crystallization of 11-Beta-Hydroxysteroid Dehydrogenase type 1

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San Diego, CA, United States of America

Mark Hilgers