title: Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors.
abstract: A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Haffner
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Boros
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Cadilla
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Carpenter
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: David
authors.initials: D
authors.lastname: Cowan
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Wallace
authors.initials: W
authors.lastname: Harrington
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Henke
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jeune
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Istvan
authors.initials: I
authors.lastname: Kaldor
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Naphtali
authors.initials: N
authors.lastname: Milliken
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Kim G
authors.initials: KG
authors.lastname: Petrov
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Preugschat
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Christie
authors.initials: C
authors.lastname: Schulte
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Barry G
authors.initials: BG
authors.lastname: Shearer
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Shearer
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Smalley
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: J Darren
authors.initials: JD
authors.lastname: Stuart
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Ulrich
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000032:analysis / Q000097:blood / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D015363:Quinolones; D013844:Thiazoles; D009243:NAD; D051997:ADP-ribosyl Cyclase 1