Sunovion

About: Sunovion is a company organization based out in London, United Kingdom. It is known for research contribution in the topics: Lurasidone & Placebo. The organization has 572 authors who have published 1022 publications receiving 18488 citations. The organization is also known as: Sunovion Pharmaceuticals, Inc..

Structural, Kinetic, and Pharmacodynamic Mechanisms of d-Amino Acid Oxidase Inhibition by Small Molecules

Abstract: We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2–4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100–200 nM) and slow release kinetics (k < 0.01 s–1) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circ...

Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5.

Abstract: A novel series of diaryl bicyclic azole-amines that are potent selective negative modulators of metabotropic glutamate receptor 5 (mGluR5) were identified through rational design. An initial hit compound 5a of modest potency (IC(50) = 1.2 μM) was synthesized. Evaluation of structure-activity relationships (SAR) on the left-hand side of the molecule revealed a preference for a 2-substituted pyridine group linked directly to the central heterocycle. Variation of the central azolo-amine portion of the molecule revealed a preference for the [4,5-c]-oxazoloazepine scaffold, while right-hand side variants showed a preference for ortho- and meta-substituted benzene rings linked directly to the tertiary amine of the saturated heterocycle. These iterations led to the synthesis of 29b, a potent (IC(50) = 16 nM) and selective negative modulator that showed good brain penetrance, high receptor occupancy, and a duration of action greater than 1 h in rat when administered intraperitoneally. Formal PK studies in rat and Rhesus monkey revealed a short half-life that was attributable to high first-pass clearance.

Relationship between crevicular aspartate aminotransferase levels and periodontal disease progression.

Abstract: Background: Aspartate aminotransferase (AST), an enzyme released from necrotic cells, has been identified in gingival crevicular fluid (GCF), and elevated levels are associated with periodontal tissue destruction. The aim of this study was to examine the relationship between elevated GCF levels of AST and periodontal disease progression. Methods: Over a 12-month period, 8 to 10 interproximal sites in 41 periodontitis subjects (PS) and 15 healthy subjects (HS) were monitored. Clinical measurements included relative attachment level (RAL), probing depth, and bleeding on probing (BOP). Semiquantitative levels of GCF AST (<800 µIU, ≥800 µIU, and ≥1,200 µIU) were determined using a chairside assay. At the 6- and 12-month visits, scaling and root planing and prophylaxis were performed in the PS and HS, respectively. Sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were calculated for 2 diagnostic criteria (AST ≥800 µIU, AST ≥1,200 µIU) utilizing 4 thresholds of di...

Benzo[d]isoxazol-3-ol DAAO inhibitors

Abstract: Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia, or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutic amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: I wherein Z1 is N or CR3; Z2 is N or CR4; Z3 is O or S; A is hydrogen, alkyl or M+; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and SO2NH2; R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl; at least one of R1, R2, R3 and R4 is other than hydrogen; and at least one of Z1 and Z2 is other than N.