title: Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy.
abstract: A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models.
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States. Electronic address: emanuele_perola@vrtx.com.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Ronkin
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Arnaud
authors.initials: A
authors.lastname: LeTiran
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Deininger
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Shi-Kai
authors.initials: SK
authors.lastname: Tian
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Drumm
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, United States.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tessier
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology; D001798:Blood Proteins / Q000378:metabolism; D027081:DNA Gyrase / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051381:Rats; D059005:Topoisomerase II Inhibitors / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase
keywords: Antibacterial; Gyrase B; Predictive models; Protein binding; Serum shift; Topoisomerase IV