ABSTRACT
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , 5-Lipoxygenase-Activating Proteins/chemistry , Alkanes/chemical synthesis , Anti-Allergic Agents/chemical synthesis , Benzene Derivatives/chemical synthesis , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacokinetics , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacology , 5-Lipoxygenase-Activating Proteins/metabolism , Alkanes/pharmacokinetics , Alkanes/pharmacology , Animals , Anti-Allergic Agents/pharmacokinetics , Anti-Allergic Agents/pharmacology , Benzene Derivatives/pharmacokinetics , Benzene Derivatives/pharmacology , Humans , Inhibitory Concentration 50 , Injections, Intravenous , Neutrophils/drug effects , Neutrophils/metabolism , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A synthetic strategy to prepare peptide-polymer conjugates with precise sites of attachment is described. Amino acids modified with atom transfer radical polymerization (ATRP) initiators for the polymerization of styrenes and methacrylates were prepared. Fmoc-4-(1-chloroethyl)-phenylalanine (5) was synthesized in four steps from Fmoc-tyrosine. HATU-mediated amidation with glycine-OMe resulted in dipeptide (6). The initiator was effective for Cu(I)/bipyridine mediated bulk polymerization of styrene. Kinetic studies indicated a controlled polymerization, with high conversion (97%), and a polydispersity index (PDI) of 1.25. Fmoc-O-(2-bromoisobutyryl)-serine tert-butyl ester (10) was synthesized from Fmoc-Ser(OTrt)-OH in three steps. This initiator was employed in the ATRP of 2-hydroxyethyl methacrylate (HEMA), and kinetic studies indicated a controlled polymerization. Different monomer to initiator ratios resulted in poly(HEMA) of different molecular weights and narrow PDIs (1.14-1.25). Conversions were between 70 and 99%. HEMA modified with N-acetyl-D-glucosamine (GlcNAc) was also polymerized to 84% conversion and the resulting PDI was 1.19. The t-butyl ester protecting group of 10 was removed, and the resulting amino acid (11) was incorporated into VM(11)VVQTK by standard solid-phase peptide synthesis. Polymerization resulted in the glycopolymer-peptide conjugate in 93% conversion and a PDI of 1.14.
Subject(s)
Amino Acids/chemistry , Peptides/chemical synthesis , Polymers/chemical synthesis , Amino Acids/chemical synthesis , Dipeptides/chemical synthesis , Dipeptides/chemistry , Fluorenes/chemical synthesis , Fluorenes/chemistry , Methacrylates/chemistry , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Polymethacrylic Acids/chemistry , Polystyrenes/chemical synthesis , Serine/analogs & derivatives , Serine/chemical synthesis , Serine/chemistry , Styrenes/chemistryABSTRACT
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.
