title: Solution-phase parallel synthesis of carbamates as gamma-secretase inhibitors.
abstract: A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Vaccaro
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terracina
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Pissarnitski
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D044367:Phase Transition; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D012996:Solutions; D053829:Amyloid Precursor Protein Secretases