Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor.
We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Mihirbaran
0000-0002-7870-7271
M
Mandal
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Zheng
Z
Tan
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Christina
C
Madsen-Duggan
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Alexei V
0000-0002-5968-9151
AV
Buevich
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
John P
JP
Caldwell
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Reynalda
R
Dejesus
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Amy
A
Flattery
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Charles G
CG
Garlisi
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Charles
C
Gill
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Sookhee Nicole
SN
Ha
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Ginny
G
Ho
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Sandra
S
Koseoglu
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Marc
M
Labroli
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Kallol
K
Basu
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Sang Ho
SH
Lee
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Lianzhu
L
Liang
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Jenny
J
Liu
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Todd
T
Mayhood
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Debra
D
McGuinness
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
David G
DG
McLaren
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Xiujuan
X
Wen
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Emma
E
Parmee
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Diane
D
Rindgen
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Terry
T
Roemer
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Payal
P
Sheth
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Paul
P
Tawa
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
James
J
Tata
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Christine
C
Yang
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Shu-Wei
SW
Yang
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Li
L
Xiao
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Hao
H
Wang
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Christopher
C
Tan
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Haifeng
H
Tang
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Paul
P
Walsh
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Erika
E
Walsh
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Jin
J
Wu
Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Jing
J
Su
D000818:Animals; D005260:Female; D008055:Lipids / Q000737:chemistry*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D054852:Small Molecule Libraries; D012995:Solubility; D013329:Structure-Activity Relationship
D008055:Lipids; D054852:Small Molecule Libraries