title: Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a multi- and extensively-drug-resistant anti-tuberculosis agent.
abstract: A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log10 reduction at 10 mg/kg dosing level, respectively) in mouse lung.
authors.affiliation: Medicinal and Bioorganic Chemistry Group, ‡Antibacterial Drug Discovery Group, and §Drug Metabolism and Pharmacokinetics Group, Institut Pasteur Korea , 16 Daewnagpangyo-ro, 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Kang
authors.forename: Ryang Yeo
authors.initials: RY
authors.lastname: Kim
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Seo
authors.forename: Saeyeon
authors.initials: S
authors.lastname: Lee
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Mooyoung
authors.initials: M
authors.lastname: Seo
authors.forename: Jeong Jea
authors.initials: JJ
authors.lastname: Seo
authors.forename: Yoonae
authors.initials: Y
authors.lastname: Ko
authors.forename: Inhee
authors.initials: I
authors.lastname: Choi
authors.forename: Jichan
authors.initials: J
authors.lastname: Jang
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Nam
authors.forename: Seijin
authors.initials: S
authors.lastname: Park
authors.forename: Hwankyu
authors.initials: H
authors.lastname: Kang
authors.forename: Hyung Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jungjun
authors.initials: J
authors.lastname: Kim
authors.forename: Sujin
authors.initials: S
authors.lastname: Ahn
authors.forename: Kevin
authors.initials: K
authors.lastname: Pethe
authors.forename: Kiyean
authors.initials: K
authors.lastname: Nam
authors.forename: Zaesung
authors.initials: Z
authors.lastname: No
authors.forename: Jaeseung
authors.initials: J
authors.lastname: Kim
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D007093:Imidazoles; D011725:Pyridines