Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia
Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective...
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| Published in | ACS medicinal chemistry letters Vol. 3; no. 3; pp. 187 - 192 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
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American Chemical Society
08.03.2012
Amer Chemical Soc |
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| Abstract | Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and 13C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure–activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors. |
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| AbstractList | Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors. Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors. Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and 13C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure–activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors. Kynurenine aminotransferase (KAT) 11 has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT H. An X-ray crystal structure and C-13 NMR studies of PF-04859989 bound to KAT H have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors. Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and 13 C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure–activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors. |
| Author | Pandit, Jayvardhan Ghosh, Somraj Rong, SuoBao McAllister, Laura A Strick, Christine A Hayward, Matthew M Salafia, Michelle A Tuttle, Jamison B Claffey, Michelle M Gan, Xinmin Parikh, Vinod D Verhoest, Patrick R Anderson, Marie Kim, Ji-Young Campbell, Brian M Zawadzke, Laura E Dounay, Amy B Paradis, Vanessa Evrard, Edelweiss Schuyten, Katherine Reese, Matthew R Valentine, James Bechle, Bruce M Wang, Hong Evdokimov, Artem Fonseca, Kari R Horner, Weldon |
| AuthorAffiliation | Pfizer Worldwide Research and Development |
| AuthorAffiliation_xml | – name: Pfizer Worldwide Research and Development |
| Author_xml | – sequence: 1 givenname: Amy B surname: Dounay fullname: Dounay, Amy B email: amy.dounay@pfizer.com – sequence: 2 givenname: Marie surname: Anderson fullname: Anderson, Marie – sequence: 3 givenname: Bruce M surname: Bechle fullname: Bechle, Bruce M – sequence: 4 givenname: Brian M surname: Campbell fullname: Campbell, Brian M – sequence: 5 givenname: Michelle M surname: Claffey fullname: Claffey, Michelle M – sequence: 6 givenname: Artem surname: Evdokimov fullname: Evdokimov, Artem – sequence: 7 givenname: Edelweiss surname: Evrard fullname: Evrard, Edelweiss – sequence: 8 givenname: Kari R surname: Fonseca fullname: Fonseca, Kari R – sequence: 9 givenname: Xinmin surname: Gan fullname: Gan, Xinmin – sequence: 10 givenname: Somraj surname: Ghosh fullname: Ghosh, Somraj – sequence: 11 givenname: Matthew M surname: Hayward fullname: Hayward, Matthew M – sequence: 12 givenname: Weldon surname: Horner fullname: Horner, Weldon – sequence: 13 givenname: Ji-Young surname: Kim fullname: Kim, Ji-Young – sequence: 14 givenname: Laura A surname: McAllister fullname: McAllister, Laura A – sequence: 15 givenname: Jayvardhan surname: Pandit fullname: Pandit, Jayvardhan – sequence: 16 givenname: Vanessa surname: Paradis fullname: Paradis, Vanessa – sequence: 17 givenname: Vinod D surname: Parikh fullname: Parikh, Vinod D – sequence: 18 givenname: Matthew R surname: Reese fullname: Reese, Matthew R – sequence: 19 givenname: SuoBao surname: Rong fullname: Rong, SuoBao – sequence: 20 givenname: Michelle A surname: Salafia fullname: Salafia, Michelle A – sequence: 21 givenname: Katherine surname: Schuyten fullname: Schuyten, Katherine – sequence: 22 givenname: Christine A surname: Strick fullname: Strick, Christine A – sequence: 23 givenname: Jamison B surname: Tuttle fullname: Tuttle, Jamison B – sequence: 24 givenname: James surname: Valentine fullname: Valentine, James – sequence: 25 givenname: Hong surname: Wang fullname: Wang, Hong – sequence: 26 givenname: Laura E surname: Zawadzke fullname: Zawadzke, Laura E – sequence: 27 givenname: Patrick R surname: Verhoest fullname: Verhoest, Patrick R |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24900455$$D View this record in MEDLINE/PubMed |
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| Keywords | hydroxamic acid KAT II kynurenine aminotransferase kynurenic acid ACID COVALENT CRYSTAL-STRUCTURE CEREBROSPINAL-FLUID EXTRACELLULAR GLUTAMATE STRATEGIES ALIGNMENT PATHWAY ELEVATED LEVELS |
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| Snippet | Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and... Kynurenine aminotransferase (KAT) 11 has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and... Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and... |
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| Title | Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia |
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