ABSTRACT
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Subject(s)
Benzopyrans/chemistry , Enzyme Inhibitors/chemistry , Esterases/antagonists & inhibitors , Animals , Benzopyrans/pharmacokinetics , Benzopyrans/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Esterases/metabolism , Femur/physiology , Half-Life , Humans , Inhibitory Concentration 50 , Male , Mice , Osteoporosis/drug therapy , Osteoporosis/physiopathology , Protein Binding , Structure-Activity RelationshipABSTRACT
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Subject(s)
Amides/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Fatty Acid Desaturases/antagonists & inhibitors , Metabolic Syndrome/drug therapy , Amides/chemical synthesis , Amides/chemistry , Animals , Delta-5 Fatty Acid Desaturase , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fatty Acid Desaturases/metabolism , Humans , Liver/enzymology , Metabolic Syndrome/enzymology , Metabolic Syndrome/metabolism , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
The incidence of cognitive disorders such as Alzheimer's disease continues to increase unabated. While cures for such diseases have eluded investigators, progress is being made on alleviating certain symptoms of these diseases. Mouse knockouts of the proline transporter (PROT), a high affinity Na(+)/Cl(-)-dependent transporter, indicated its potential as a novel therapeutic target for cognition improvement. Herein we report our investigation into a novel class of PROT inhibitors.
Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Cognition Disorders/drug therapy , Small Molecule Libraries/pharmacology , Amino Acid Transport Systems, Neutral/deficiency , Amino Acid Transport Systems, Neutral/metabolism , Animals , Biological Transport/drug effects , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Humans , Mice , Mice, Knockout , Molecular Structure , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.
