| Literature DB >> 32197094 |
Daigo Inoyama1, Divya Awasthi1, Glenn C Capodagli2, Kholiswa Tsotetsi3, Paridhi Sukheja3, Matthew Zimmerman4, Shao-Gang Li1, Ravindra Jadhav1, Riccardo Russo3, Xin Wang1, Courtney Grady3, Todd Richmann3, Riju Shrestha3, Liping Li3, Yong-Mo Ahn1, Hsin Pin Ho Liang4, Marizel Mina4, Steven Park4, David S Perlin4, Nancy Connell3, Véronique Dartois4, David Alland5, Matthew B Neiditch6, Pradeep Kumar7, Joel S Freundlich8.
Abstract
Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.Entities:
Keywords: JSF-3285; KasA; Mycobacterium tuberculosis; antitubercular; pharmacokinetics; structure-based design
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Year: 2020 PMID： 32197094 PMCID： PMC7245553 DOI： 10.1016/j.chembiol.2020.02.007
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116