ABSTRACT
Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.
Subject(s)
Benzamides/chemistry , Benzimidazoles/chemistry , Histamine H3 Antagonists/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3 , Animals , Benzamides/blood , Benzamides/metabolism , Benzimidazoles/blood , Benzimidazoles/metabolism , Caco-2 Cells , Cell Line , Histamine H3 Antagonists/blood , Histamine H3 Antagonists/metabolism , Humans , Indoles/blood , Indoles/chemistry , Indoles/metabolism , Protein Binding , Pyrrolidines/blood , Pyrrolidines/metabolism , Rats , Receptors, Histamine H3/blood , Receptors, Histamine H3/metabolismABSTRACT
A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Guanidines/chemical synthesis , Guanidines/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Crystallography, X-Ray , Drug Design , Indicators and Reagents , Models, Molecular , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Inflammation/drug therapy , Inflammation/immunology , Pyrazoles/therapeutic use , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/immunology , Chronic Disease , Humans , Ligands , Molecular Structure , Structure-Activity RelationshipABSTRACT
Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Arthritis, Rheumatoid/drug therapy , Indazoles/chemical synthesis , Phenols/chemical synthesis , Receptors, Estrogen/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Cell Line , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/drug effects , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/chemistry , Estrogen Receptor beta/drug effects , Estrogen Receptor beta/metabolism , Humans , Indazoles/chemistry , Indazoles/pharmacology , Ligands , Mice , Mice, Inbred C57BL , Models, Molecular , NF-kappa B/biosynthesis , NF-kappa B/genetics , Phenols/chemistry , Phenols/pharmacology , Rats , Rats, Inbred Lew , Receptors, Estrogen/chemistry , Receptors, Estrogen/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a series of human beta3 adrenoreceptor agonists based on a template derived from a common pharmacophore coupled with 4-aminomethylpiperidine is described. Potent and selective agents were identified such as 26 that was in vitro active in CHO cells expressing human beta3-AR (EC50=49 nM, IA=1.1), and in vivo active in a transgenic mouse model.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Indicators and Reagents , Mice , Mice, Transgenic , Receptors, Adrenergic, beta-3/genetics , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a series of beta3 adrenoreceptor agonists based on a novel template derived from 4-aminomethylpiperidine coupled with a common pharmacophore, arylethylamine, is described. This combination led to the identification of human beta3 adrenoreceptor agonists with in vivo activity in a transgenic mouse model.
