title: Azabenzthiazole inhibitors of leukotriene A₄ hydrolase.
abstract: Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 μM.
authors.affiliation: Janssen Research & Development LLC, 3210 Merryfield Row, San Diego, CA 92121, United States. vtanis@its.jnj.com
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Tanis
authors.forename: Genesis M
authors.initials: GM
authors.lastname: Bacani
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blevitt
authors.forename: Christa C
authors.initials: CC
authors.lastname: Chrovian
authors.forename: Shelby
authors.initials: S
authors.lastname: Crawford
authors.forename: Aimee
authors.initials: A
authors.lastname: De Leon
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fourie
authors.forename: Laurent
authors.initials: L
authors.lastname: Gomez
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Grice
authors.forename: Krystal
authors.initials: K
authors.lastname: Herman
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Kearney
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Landry-Bayle
authors.forename: Alice
authors.initials: A
authors.lastname: Lee-Dutra
authors.forename: Jay
authors.initials: J
authors.lastname: Nelson
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santillán
authors.forename: John J M
authors.initials: JJ
authors.lastname: Wiener
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xue
authors.forename: Arlene L
authors.initials: AL
authors.lastname: Young
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C581053:azabenzthiazole; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase