ABSTRACT
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.
Subject(s)
Antipsychotic Agents/chemistry , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Triazoles/chemistry , Allosteric Regulation/drug effects , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/metabolism , Cognition/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Microsomes/metabolism , Rats , Receptor, Metabotropic Glutamate 5/metabolism , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/pharmacologyABSTRACT
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
Subject(s)
Benzamides/chemical synthesis , Combinatorial Chemistry Techniques/methods , Piperazines/chemical synthesis , Pyrimidines/chemical synthesis , Benzamides/chemistry , Combinatorial Chemistry Techniques/instrumentation , Imatinib Mesylate , Molecular Structure , Piperazines/chemistry , Pyrimidines/chemistryABSTRACT
Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API's).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Fusion Proteins, bcr-abl/antagonists & inhibitors , Piperazines/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Thiazoles/chemical synthesis , Antineoplastic Agents/chemistry , Benzamides/chemistry , Benzamides/pharmacology , Dasatinib , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Piperazines/chemistry , Piperazines/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.
Subject(s)
Antineoplastic Agents/chemical synthesis , Piperazines/chemical synthesis , Pyrimidines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Benzamides , Dimethylamines/chemistry , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazine , Piperazines/chemistry , Piperazines/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic useABSTRACT
A fully automated flow-through process for the production of secondary sulfonamides is presented. Primary sulfonamides were monoalkylated using a two-step "catch and release" protocol to generate library products of high purity. The automated flow synthesis platform incorporates four independent reactor columns and is able to perform automated column regeneration. A 48-member sulfonamide library was prepared as two 24-member sublibraries, affording library compounds in good yields and high purities without the need for further column chromatographic purification.
