ABSTRACT
A novel series of potent blockers of the monocarboxylate transporter, MCT1, is disclosed. From very potent but lipophilic lead compounds, systematic changes to all parts of the molecule, targeting reduction in log D, afforded compounds with significantly improved overall properties. These compounds show potent immunomodulatory activity.
Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 Enzyme System/metabolism , Herpesviridae/drug effects , Immunologic Factors/pharmacology , Monocarboxylic Acid Transporters/antagonists & inhibitors , Symporters/antagonists & inhibitors , T-Lymphocytes/drug effects , Animals , Aryl Hydrocarbon Hydroxylases/immunology , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/immunology , Graft vs Host Disease/immunology , Herpesviridae/immunology , Herpesviridae/metabolism , Humans , Immunologic Factors/chemistry , Monocarboxylic Acid Transporters/immunology , Monocarboxylic Acid Transporters/metabolism , Symporters/immunology , Symporters/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismSubject(s)
Chromones/pharmacology , Lung/physiology , Muscle Contraction/drug effects , Muscle, Smooth/physiology , SRS-A/antagonists & inhibitors , Animals , Bronchi/physiology , Guinea Pigs , Humans , Lung/drug effects , Muscle, Smooth/drug effects , SRS-A/pharmacology , Structure-Activity Relationship , Trachea/physiologyABSTRACT
A series of substituted chromone-2-carboxylic acids was synthesized and tested as antagonists of SRS-A induced contractions of isolated guinea pig ileum. This work led to the discovery of sodium 7-[3-(4-acetyl-3hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (FPL 55712) which is the first reported specific antagonist of SRS-A. Some structural requirements for biological activity within this series are discussed.
Subject(s)
Chromones/chemical synthesis , SRS-A/antagonists & inhibitors , Animals , Chromones/pharmacology , Guinea Pigs , In Vitro Techniques , Methods , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Structure-Activity RelationshipABSTRACT
The synthesis and antiallergic activity of a number of benzodipyrandicarboxylic acids are described. Antiallergic activity of the compounds was determined using the homologous passive cutaneous anaphylaxis (PCA) reaction in the rat. The structural requirements for activity in the PCA screen are discussed. In this test system the linear benzodipyrans are more active than their angular analogues.
