MK-5204: An orally active β-1,3-glucan synthesis inhibitor.

Autor: Apgar JM; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: james_apgar@merck.com., Wilkening RR; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Parker DL Jr; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Meng D; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Wildonger KJ; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Sperbeck D; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Greenlee ML; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Balkovec JM; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Flattery AM; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Abruzzo GK; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Galgoci AM; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Giacobbe RA; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Gill CJ; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Hsu MJ; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Liberator P; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Misura AS; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Motyl M; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Kahn JN; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Powles M; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Racine F; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Dragovic J; Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Fan W; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA., Kirwan R; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA., Lee S; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA., Liu H; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA., Mamai A; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA., Nelson K; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA., Peel M; Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Sep 01; Vol. 30 (17), pp. 127357. Date of Electronic Publication: 2020 Jun 19.
DOI: 10.1016/j.bmcl.2020.127357
Abstrakt: Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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