ABSTRACT
The discovery of potent novel pyrazole containing group X secreted phospholipase A2 inhibitors via structure based virtual screening is reported. Docking was applied on a large set of in-house fragment collection and pharmacophore feature matching was used to filter docking poses. The selected virtual screening hits was run in NMR screening, a potent pyrazole containing fragment hit was identified and confirmed by its complex X-ray structure and the following biochemical assay result. Expansion on the fragment hit has led to further improvement of potency while maintaining high ligand efficiency, thus supporting the further development of this chemical series.
Subject(s)
Group X Phospholipases A2/chemistry , Phospholipase A2 Inhibitors/chemistry , Pyrazoles/chemistry , Binding Sites , Databases, Protein , Drug Evaluation, Preclinical , Group X Phospholipases A2/metabolism , Humans , Molecular Docking Simulation , Phospholipase A2 Inhibitors/metabolism , Protein Structure, Tertiary , Pyrazoles/metabolismABSTRACT
Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y12 receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine 3 and azetidine 13 dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED50 values of 3.0 and 10 µg/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 µg/kg/min for 3 and 13, respectively. Thus, the therapeutic index (TI) was ≥ 10 for both compounds. On the basis of these data, compound 3 was progressed into human clinical trials as candidate drug AZD1283.
Subject(s)
Niacin/analogs & derivatives , Receptors, Purinergic P2Y12/drug effects , Sulfonamides/pharmacology , Thrombosis/prevention & control , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Humans , Niacin/pharmacologyABSTRACT
Studies of structure-activity relationships for the linker in a new series of metabotropic glutamate receptor 5 antagonists are presented together with in vitro and in vivo pharmacokinetic data.
Subject(s)
Alkynes/chemistry , Alkynes/pharmacology , Cross-Linking Reagents/chemistry , Pyridines/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Alkynes/chemical synthesis , Alkynes/pharmacokinetics , Animals , Liver/drug effects , Liver/metabolism , Molecular Structure , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
Synthesis and some structure-activity relationships for a new series of propargyl ethers as mGluR5 antagonists are reported.
Subject(s)
Alkynes/chemistry , Alkynes/pharmacology , Pyridines/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Alkynes/chemical synthesis , Inhibitory Concentration 50 , Molecular Structure , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.
Subject(s)
Pyrimidines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thionucleosides/pharmacology , Animals , Cell Line , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Liver/drug effects , Microsomes/drug effects , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Receptor, Metabotropic Glutamate 5 , Stereoisomerism , Structure-Activity Relationship , Thionucleosides/chemical synthesis , Thionucleosides/chemistryABSTRACT
Fenobam (1) was developed by McNeil Laboratories as an anxiolytic agent with an unknown molecular target in the late 1970s. In a recent publication, it was revealed that fenobam is a non-competitive mGluR5 antagonist. Herein, we present the structure-activity relationship of fenobam and its analogues and similarities between the SAR of mGluR5 antagonism and the SAR of CNS properties originally reported by McNeil are discussed.
