ABSTRACT
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
A series of potent piperidine-linked cytosine derivatives were prepared as inhibitors of deoxycytidine kinase (dCK). Compound 9h was discovered to be a potent inhibitor of dCK and shows a good combination of cellular potency and pharmacokinetic parameters. Compound 9h blocks the incorporation of radiolabeled cytosine into mouse T-cells in vitro, as well as in vivo in mice following a T-cell challenge.
Subject(s)
Deoxycytidine Kinase/antagonists & inhibitors , Flucytosine/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Drug Design , Flucytosine/chemical synthesis , Flucytosine/chemistry , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.
Subject(s)
Deoxycytidine Kinase/antagonists & inhibitors , Deoxycytidine/analogs & derivatives , Drug Design , Protein Kinase Inhibitors/pharmacology , Deoxycytidine/chemical synthesis , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. Here we describe the discovery of substituted triazines as a novel class of tryptophan hydroxylase inhibitors. This class of TPH inhibitors can selectively reduce serotonin levels in murine intestine after oral administration without affecting levels in the brain. These TPH inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.