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 IC50 of 125 nM in an enzyme assay and p...

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Published inJournal of medicinal chemistry Vol. 60; no. 9; pp. 3851 - 3865
Main Authors Mandal, Mihirbaran, Tan, Zheng, Madsen-Duggan, Christina, Buevich, Alexei V, Caldwell, John P, Dejesus, Reynalda, Flattery, Amy, Garlisi, Charles G, Gill, Charles, Ha, Sookhee Nicole, Ho, Ginny, Koseoglu, Sandra, Labroli, Marc, Basu, Kallol, Lee, Sang Ho, Liang, Lianzhu, Liu, Jenny, Mayhood, Todd, McGuinness, Debra, McLaren, David G, Wen, Xiujuan, Parmee, Emma, Rindgen, Diane, Roemer, Terry, Sheth, Payal, Tawa, Paul, Tata, James, Yang, Christine, Yang, Shu-Wei, Xiao, Li, Wang, Hao, Tan, Christopher, Tang, Haifeng, Walsh, Paul, Walsh, Erika, Wu, Jin, Su, Jing
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 11.05.2017
Amer Chemical Soc
Subjects
Animals
Chemistry, Medicinal
Female
Life Sciences & Biomedicine
Lipids - chemistry
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - growth & development
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Pharmacology & Pharmacy
Science & Technology
Small Molecule Libraries
Solubility
Structure-Activity Relationship
IN-VITRO
ANALOGS
WALL TEICHOIC-ACID
CHARGES
MRSA
OXAZOLIDINONES
DISCOVERY
CHALLENGES
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Abstract 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 IC50 of 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.
AbstractList 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 IC50 of 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.
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 IC of 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.
Author Ha, Sookhee Nicole
Flattery, Amy
Rindgen, Diane
Sheth, Payal
Labroli, Marc
Wen, Xiujuan
Walsh, Erika
Buevich, Alexei V
Dejesus, Reynalda
Caldwell, John P
Ho, Ginny
Mayhood, Todd
Parmee, Emma
McGuinness, Debra
Tata, James
Koseoglu, Sandra
Yang, Christine
Madsen-Duggan, Christina
Xiao, Li
Wu, Jin
Tawa, Paul
Tan, Zheng
Lee, Sang Ho
Roemer, Terry
Garlisi, Charles G
Yang, Shu-Wei
Mandal, Mihirbaran
Tang, Haifeng
Liu, Jenny
Walsh, Paul
Basu, Kallol
McLaren, David G
Gill, Charles
Su, Jing
Tan, Christopher
Liang, Lianzhu
Wang, Hao
AuthorAffiliation Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
In Vitro Pharmacology
Early Discovery Bacteriology
In Vivo Pharmacology
Global Chemistry
Discovery Pharmaceutical Sciences
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28322556$$D View this record in MEDLINE/PubMed
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Keywords IN-VITRO
ANALOGS
WALL TEICHOIC-ACID
CHARGES
MRSA
OXAZOLIDINONES
DISCOVERY
CHALLENGES
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Snippet We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage...
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SubjectTerms Animals
Chemistry, Medicinal
Female
Life Sciences & Biomedicine
Lipids - chemistry
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - growth & development
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Pharmacology & Pharmacy
Science & Technology
Small Molecule Libraries
Solubility
Structure-Activity Relationship
Title Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor
URI http://dx.doi.org/10.1021/acs.jmedchem.7b00113
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https://www.ncbi.nlm.nih.gov/pubmed/28322556
https://search.proquest.com/docview/1879665214
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