Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

Autor: Cohen F; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Aggen JB; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Andrews LD; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Assar Z; Cayman Chemical Co., 1180 East Ellsworth, Ann Arbor, MI, 48108, USA., Boggs J; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Choi T; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Dozzo P; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Easterday AN; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Haglund CM; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Hildebrandt DJ; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Holt MC; Cayman Chemical Co., 1180 East Ellsworth, Ann Arbor, MI, 48108, USA., Joly K; Plato BioPharma Inc., 7581 West 103rd Avenue, Unit 300, Westminster, CO, 80021, USA., Jubb A; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Kamal Z; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Kane TR; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Konradi AW; Konradi Molecular, 30 Victoria Road, Burlingame, CA, 94010, USA., Krause KM; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Linsell MS; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Machajewski TD; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Miroshnikova O; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Moser HE; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Nieto V; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Phan T; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Plato C; Plato BioPharma Inc., 7581 West 103rd Avenue, Unit 300, Westminster, CO, 80021, USA., Serio AW; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Seroogy J; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Shakhmin A; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Stein AJ; Cayman Chemical Co., 1180 East Ellsworth, Ann Arbor, MI, 48108, USA., Sun AD; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Sviridov S; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Wang Z; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Wlasichuk K; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA., Yang W; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Zhou X; Pharmaron Inc., 6 Tai-He Road, BDA, Beijing, 100176, China., Zhu H; Nanosyn Inc., 3100 Central Expressway, Santa Clara, CA, 95051, USA., Cirz RT; Achaogen Inc., 1 Tower Place, Suite 400, South San Francisco, CA, 94080, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2019 Aug 20; Vol. 14 (16), pp. 1560-1572. Date of Electronic Publication: 2019 Aug 05.
DOI: 10.1002/cmdc.201900287
Abstrakt: UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn 2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL -1 for parenteral administration and conversion into the active drug with a t 1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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