Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099)

Gregory S Basarab; Pamela J Hill; C Edwin Garner; Ken Hull; Oluyinka Green; Brian A Sherer; P Brian Dangel; John I Manchester; Shanta Bist; Sheila Hauck; Fei Zhou; Maria Uria-Nickelsen; Ruth Illingworth; Richard Alm; Mike Rooney; Ann E Eakin

doi:10.1021/jm500462x

Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099)

J Med Chem. 2014 Jul 24;57(14):6060-82. doi: 10.1021/jm500462x. Epub 2014 Jul 8.

Authors

Gregory S Basarab¹, Pamela J Hill, C Edwin Garner, Ken Hull, Oluyinka Green, Brian A Sherer, P Brian Dangel, John I Manchester, Shanta Bist, Sheila Hauck, Fei Zhou, Maria Uria-Nickelsen, Ruth Illingworth, Richard Alm, Mike Rooney, Ann E Eakin

Affiliation

¹ Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.

PMID: 24959892
DOI: 10.1021/jm500462x

Abstract

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

MeSH terms

Adenosine Triphosphatases / antagonists & inhibitors
Adenosine Triphosphatases / metabolism
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Crystallography, X-Ray
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Mice
Mice, Knockout
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Rats
Rats, Wistar
Staphylococcal Infections / drug therapy*
Staphylococcus aureus / drug effects*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*

Substances

2-(4-((3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino)-3-methoxy-1-piperidyl)-4-((2-methoxy-1-methylethyl)carbamoyl)thiazole-5-carboxylic acid
Amides
Anti-Bacterial Agents
Pyrroles
Thiazoles
Topoisomerase II Inhibitors
Adenosine Triphosphatases