title: Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway.
abstract: The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan (TRP) and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KAT II). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors are being investigated as potential treatments for neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. KAT II inhibitors have been proposed in new therapeutic approaches toward psychiatric and cognitive disorders, including cognitive impairment associated with schizophrenia. Numerous medicinal chemistry studies are currently aimed at the design of novel, potent, and selective inhibitors for each of these enzymes. The emerging opportunities and significant challenges associated with pharmacological modulation of these enzymes will be explored in this review.
authors.affiliation: Department of Chemistry and Biochemistry, Colorado College , 14 E. Cache La Poudre Street, Colorado Springs, Colorado 80903, United States.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Dounay
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
authors.forename: Jamison B
authors.initials: JB
authors.lastname: Tuttle
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002493:Central Nervous System Diseases / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D000637:Transaminases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D050601:Kynurenine 3-Monooxygenase; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase