title: Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential prodrugs of indazoles.
abstract: A new oxazole scaffold showing great promise in HIV-1 inhibition has been discovered by cell-based screening of an in-house library and scaffold modification. Follow-up SAR study focusing on the 5-aryl substituent of the oxazole core has identified 4k (EC50=0.42μM, TI=50) as a potent inhibitor. However, the analogues suffered from poor aqueous solubility. To address this issue, we have developed broadly applicable potential prodrugs of indazoles. Among them, N-acyloxymethyl analogue 11b displayed promising results (i.e., increased aqueous solubility and susceptibility to enzymatic hydrolysis). Further studies are warranted to fully evaluate the analogues as the potential prodrugs with improved physiochemical and PK properties.
authors.affiliation: Myrexis Inc., 305 Chipeta Way, Salt Lake City, UT 84108, United States. seho.kimkim@gmail.com
authors.forename: Se-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Benjamin
authors.initials: B
authors.lastname: Markovitz
authors.forename: Richard
authors.initials: R
authors.lastname: Trovato
authors.forename: Brett R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Harry
authors.initials: H
authors.lastname: Austin
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Willardsen
authors.forename: Vijay
authors.initials: V
authors.lastname: Baichwal
authors.forename: Scott
authors.initials: S
authors.lastname: Morham
authors.forename: Ashok
authors.initials: A
authors.lastname: Bajji
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D007191:Indazoles; D011355:Prodrugs