title: Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin.
abstract: The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis.
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: james_apgar@merck.com.
authors.forename: James M
authors.initials: JM
authors.lastname: Apgar
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Wilkening
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Greenlee
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Flattery
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Abruzzo
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Galgoci
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Giacobbe
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gill
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ming Jo
authors.initials: MJ
authors.lastname: Hsu
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Liberator
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Misura
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Motyl
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nielsen Kahn
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Maryann
authors.initials: M
authors.lastname: Powles
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Racine
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Dragovic
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Bahanu
authors.initials: B
authors.lastname: Habulihaz
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Fan
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Kirwan
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Lee
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mamai
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Kingsley
authors.initials: K
authors.lastname: Nelson
authors.affiliation: Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000662:veterinary; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006027:Glycosides / Q000737:chemistry*; D006207:Half-Life; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry*; D047071:beta-Glucans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D006027:Glycosides; D013729:Terpenes; D014315:Triterpenes; D047071:beta-Glucans; C421868:enfumafungin; C033363:beta-1,3-glucan; D005964:Glucosyltransferases; C040232:glucan synthase
keywords: Antifungal; Candidiasis; Enfumafungin; Oral bioavailability; β-1,3-Glucan synthesis inhibitor