ABSTRACT
Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-L-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at -20 °C as a solid, in solution, or on the resin.
Subject(s)
Biotin/chemistry , Cysteine/chemistry , Protein Methyltransferases/metabolism , Cysteine/chemical synthesis , High-Throughput Screening Assays , Kinetics , Protein Methyltransferases/chemistry , Solid-Phase Synthesis Techniques , Substrate Specificity , Trityl Compounds/chemistryABSTRACT
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Subject(s)
Benzoxazoles/pharmacokinetics , Indoles/pharmacokinetics , Memory Disorders/drug therapy , Muscarinic Agonists/pharmacokinetics , Nootropic Agents/pharmacokinetics , Receptor, Muscarinic M1/metabolism , Animals , Benzoxazoles/chemistry , Benzoxazoles/therapeutic use , Brain/metabolism , Indoles/chemistry , Indoles/therapeutic use , Muscarinic Agonists/chemistry , Muscarinic Agonists/therapeutic use , Nootropic Agents/chemistry , Nootropic Agents/therapeutic use , Oxindoles , RatsABSTRACT
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
Subject(s)
Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , CHO Cells , Chemotaxis, Leukocyte/drug effects , Computer Simulation , Cricetinae , Cricetulus , Drug Evaluation, Preclinical , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Indicators and Reagents , Myotonin-Protein Kinase , Protein Serine-Threonine Kinases/drug effects , Receptors, CCR8 , Structure-Activity Relationship , Th2 Cells/drug effectsABSTRACT
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.
