Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor

• Published in: Journal 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
• Language: English
• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00113

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.