ABSTRACT
Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg).
Subject(s)
Antidepressive Agents/chemical synthesis , Pyrazines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Binding Sites , Binding, Competitive , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Mice , Molecular Structure , Motor Activity/drug effects , Protein Binding/drug effects , Pyrazines/chemistry , Pyrazines/pharmacologyABSTRACT
We present a technique for computing activity discriminants of in vitro (pharmacological, DMPK, and safety) assays and the application to the prediction of in vitro activities of proposed synthetic targets during the lead optimization phase of drug discovery projects. This technique emulates how medicinal chemists perform SAR analysis and activity prediction. The activity discriminants that are functions of 6 commonly used medicinal chemistry descriptors can be interpreted easily by medicinal chemists. Further, visualization with Spotfire allows medicinal chemists to analyze how the query molecule is related to compounds tested previously, and to evaluate easily the relevance of the activity discriminants to the activities of the query molecule. Validation with all compounds synthesized and tested in AstraZeneca Wilmington since 2006 demonstrates that this approach is useful for prioritizing new synthetic targets for synthesis.
Subject(s)
Biological Assay/methods , Chemistry, Pharmaceutical/methods , Drug Design , Pharmaceutical Preparations/chemistry , Structure-Activity RelationshipABSTRACT
We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.
Subject(s)
Pyrazoles/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Binding, Competitive , CHO Cells , Combinatorial Chemistry Techniques , Cricetinae , Cricetulus , Drug Design , Drug Partial Agonism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Humans , Hypothermia/drug therapy , Lipidoses/chemically induced , Lipidoses/metabolism , Phospholipids/metabolism , Piperazines/adverse effects , Piperazines/chemical synthesis , Piperazines/pharmacology , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Radioligand Assay , Serotonin 5-HT1 Receptor Agonists , Structure-Activity RelationshipABSTRACT
In large-scale virtual screening (VS) campaigns, data are often computed for millions of compounds to identify leads, but there remains the task of prioritizing VS "hits" for experimental assays and the dilemma of assessing true/false positives. We present two statistical methods for mining large databases: (1) a general scoring metric based on the VS signal-to-noise level within a compound neighborhood; (2) a neighborhood-based sampling strategy for reducing database size, in lieu of property-based filters.
