Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin.

Autor: Apgar JM; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: james_apgar@merck.com., Wilkening RR; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Greenlee ML; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Balkovec JM; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Flattery AM; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Abruzzo GK; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Galgoci AM; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Giacobbe RA; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Gill CJ; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Hsu MJ; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Liberator P; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Misura AS; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Motyl M; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Nielsen Kahn J; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Powles M; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Racine F; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Dragovic J; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Habulihaz B; Merck Research Laboratories, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Fan W; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA., Kirwan R; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA., Lee S; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA., Liu H; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA., Mamai A; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA., Nelson K; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA., Peel M; Scynexis Inc., PO Box 12878, Research Triangle Park, NC 27709, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Dec 15; Vol. 25 (24), pp. 5813-8. Date of Electronic Publication: 2015 Oct 09.
DOI: 10.1016/j.bmcl.2015.10.011
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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