Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Antibacterial inhibitors of gram-positive thymidylate kinase: Structure-activity relationships and chiral preference of a new hydrophobic binding region

Kawatkar, SP and Keating, TA and Olivier, NB and Breen, JN and Green, OM and Guler, SY and Hentemann, MF and Loch, JT and McKenzie, AR and Newman, JV and Otterson, LG and Martinez-Botella, G (2014) Antibacterial inhibitors of gram-positive thymidylate kinase: Structure-activity relationships and chiral preference of a new hydrophobic binding region. Journal of Medicinal Chemistry. pp. 4584-4597.

Abstract

Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC<sub>50</sub> against S. aureus TMK and 2 mug/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses. 2014 American Chemical Society

Item Type: Article
Additional Information: NIBR author: Hentemann, MF institute: NIBR- address only contributor address: (Kawatkar, Keating, Breen, Green, Guler, Hentemann, Loch, McKenzie, Newman, Otterson, Martinez-Botella) Infection Innovative Medicines, AstraZeneca, 35 Gatehouse Drive, Waltham, Ma 02451, United States (Olivier, Breen) Discovery Sciences, AstraZeneca, 35 Gatehouse Drive, Waltham, Ma 02451, United States (Kawatkar) AstraZeneca Oncology Innovative Medicines, 35 Gatehouse Dr., Waltham, MA 02451, United States (Keating) ImmunoGen, Inc., 830 Winter St., Waltham, MA 02451, United States (Hentemann) Novartis Institutes for BioMedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, United States (Martinez-Botella) Sage Therapeutics, 215 First St., Cambridge, MA 02141, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22754

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.