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PDBsum entry 6mo4
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Hydrolase/inhibitor
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PDB id
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6mo4
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References listed in PDB file
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Key reference
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Title
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Optimization of lpxc inhibitors for antibacterial activity and cardiovascular safety.
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Authors
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F.Cohen,
J.B.Aggen,
L.D.Andrews,
Z.Assar,
J.Boggs,
T.Choi,
P.Dozzo,
A.N.Easterday,
C.M.Haglund,
D.J.Hildebrandt,
M.C.Holt,
K.Joly,
A.Jubb,
Z.Kamal,
T.R.Kane,
A.W.Konradi,
K.M.Krause,
M.S.Linsell,
T.D.Machajewski,
O.Miroshnikova,
H.E.Moser,
V.Nieto,
T.Phan,
C.Plato,
A.W.Serio,
J.Seroogy,
A.Shakhmin,
A.J.Stein,
A.D.Sun,
S.Sviridov,
Z.Wang,
K.Wlasichuk,
W.Yang,
X.Zhou,
H.Zhu,
R.T.Cirz.
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Ref.
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ChemMedChem, 2019,
14,
1560-1572.
[DOI no: ]
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PubMed id
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Abstract
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UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a
Zn2+ 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 t1/2 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.
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