title: Discovery of a novel class of orally active antifungal beta-1,3-D-glucan synthase inhibitors.
abstract: The echinocandins are a class of semisynthetic natural products that target β-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, Kenilworth, New Jersey 07033, USA. scott.walker@merck.com
authors.forename: Scott S
authors.initials: SS
authors.lastname: Walker
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.forename: Ilias
authors.initials: I
authors.lastname: Triantafyllou
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Waldman
authors.forename: Cara
authors.initials: C
authors.lastname: Mendrick
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Brown
authors.forename: Paul
authors.initials: P
authors.lastname: Mann
authors.forename: Andrew
authors.initials: A
authors.lastname: Chau
authors.forename: Reena
authors.initials: R
authors.lastname: Patel
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bauman
authors.forename: Christine
authors.initials: C
authors.lastname: Norris
authors.forename: Barry
authors.initials: B
authors.lastname: Antonacci
authors.forename: Maya
authors.initials: M
authors.lastname: Gurnani
authors.forename: Anthony
authors.initials: A
authors.lastname: Cacciapuoti
authors.forename: Paul M
authors.initials: PM
authors.lastname: McNicholas
authors.forename: Samuel
authors.initials: S
authors.lastname: Wainhaus
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.forename: Rongze
authors.initials: R
authors.lastname: Kuang
authors.forename: Robert G
authors.initials: RG
authors.lastname: Aslanian
authors.forename: Pauline C
authors.initials: PC
authors.lastname: Ting
authors.forename: Todd A
authors.initials: TA
authors.lastname: Black
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology
chemical_list: D000935:Antifungal Agents; D010879:Piperazines; D011724:Pyridazines; C062482:pyridazine; D005964:Glucosyltransferases; C040232:glucan synthase