title: Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).
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.
authors: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors: Gregory S
authors: GS
authors: Basarab
authors: Pamela J
authors: PJ
authors: Hill
authors: C Edwin
authors: CE
authors: Garner
authors: Ken
authors: K
authors: Hull
authors: Oluyinka
authors: O
authors: Green
authors: Brian A
authors: BA
authors: Sherer
authors: P Brian
authors: PB
authors: Dangel
authors: John I
authors: JI
authors: Manchester
authors: Shanta
authors: S
authors: Bist
authors: Sheila
authors: S
authors: Hauck
authors: Fei
authors: F
authors: Zhou
authors: Maria
authors: M
authors: Uria-Nickelsen
authors: Ruth
authors: R
authors: Illingworth
authors: Richard
authors: R
authors: Alm
authors: Mike
authors: M
authors: Rooney
authors: Ann E
authors: AE
authors: Eakin
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000592446:2-(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; D000577:Amides; D000900:Anti-Bacterial Agents; D011758:Pyrroles; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D000251:Adenosine Triphosphatases