A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1H‑[1,2,3]triazolo[4,5‑c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate
A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described...
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| Published in | Journal of medicinal chemistry Vol. 61; no. 1; pp. 207 - 223 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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WASHINGTON
American Chemical Society
11.01.2018
Amer Chemical Soc |
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| Abstract | A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders. |
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| AbstractList | A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED
values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders. A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structureactivity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders. A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders. |
| Author | Scott, Brian Chrovian, Christa C Deng, Xiaohu Bhattacharya, Anindya Gelin, Christine F Aluisio, Leah Lord, Brian Carruthers, Nicholas I Gallacher, David J Sepassi, Kia Peterson, Alexander A Dvorak, Curt A Coe, Kevin J Letavic, Michael A Fraser, Ian Koudriakova, Tatiana Soyode-Johnson, Akinola Schoetens, Freddy |
| AuthorAffiliation | Janssen Research & Development Janssen Research & Development, LLC |
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| Author_xml | – sequence: 1 givenname: Christa C orcidid: 0000-0002-4971-1538 surname: Chrovian fullname: Chrovian, Christa C email: cchrovia@its.jnj.com organization: Janssen Research & Development, LLC – sequence: 2 givenname: Akinola surname: Soyode-Johnson fullname: Soyode-Johnson, Akinola organization: Janssen Research & Development, LLC – sequence: 3 givenname: Alexander A surname: Peterson fullname: Peterson, Alexander A organization: Janssen Research & Development, LLC – sequence: 4 givenname: Christine F surname: Gelin fullname: Gelin, Christine F organization: Janssen Research & Development, LLC – sequence: 5 givenname: Xiaohu surname: Deng fullname: Deng, Xiaohu organization: Janssen Research & Development, LLC – sequence: 6 givenname: Curt A surname: Dvorak fullname: Dvorak, Curt A organization: Janssen Research & Development, LLC – sequence: 7 givenname: Nicholas I surname: Carruthers fullname: Carruthers, Nicholas I organization: Janssen Research & Development, LLC – sequence: 8 givenname: Brian surname: Lord fullname: Lord, Brian organization: Janssen Research & Development, LLC – sequence: 9 givenname: Ian surname: Fraser fullname: Fraser, Ian organization: Janssen Research & Development, LLC – sequence: 10 givenname: Leah surname: Aluisio fullname: Aluisio, Leah organization: Janssen Research & Development, LLC – sequence: 11 givenname: Kevin J surname: Coe fullname: Coe, Kevin J organization: Janssen Research & Development, LLC – sequence: 12 givenname: Brian surname: Scott fullname: Scott, Brian organization: Janssen Research & Development, LLC – sequence: 13 givenname: Tatiana surname: Koudriakova fullname: Koudriakova, Tatiana organization: Janssen Research & Development, LLC – sequence: 14 givenname: Freddy surname: Schoetens fullname: Schoetens, Freddy organization: Janssen Research & Development, LLC – sequence: 15 givenname: Kia surname: Sepassi fullname: Sepassi, Kia organization: Janssen Research & Development, LLC – sequence: 16 givenname: David J surname: Gallacher fullname: Gallacher, David J organization: Janssen Research & Development – sequence: 17 givenname: Anindya surname: Bhattacharya fullname: Bhattacharya, Anindya organization: Janssen Research & Development, LLC – sequence: 18 givenname: Michael A orcidid: 0000-0002-7503-0189 surname: Letavic fullname: Letavic, Michael A organization: Janssen Research & Development, LLC |
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| Keywords | RHEUMATOID-ARTHRITIS EFFICACY SAFETY PHARMACOLOGICAL CHARACTERIZATION CLICK CHEMISTRY DISEASE RECEPTOR IDENTIFICATION AZIDE |
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| Snippet | A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine... A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7... |
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| SubjectTerms | Animals Chemistry, Medicinal Cycloaddition Reaction Dogs Drug Design Humans Life Sciences & Biomedicine Male Mice Models, Molecular Molecular Conformation Pharmacology & Pharmacy Purinergic P2X Receptor Antagonists - chemical synthesis Purinergic P2X Receptor Antagonists - chemistry Purinergic P2X Receptor Antagonists - pharmacokinetics Purinergic P2X Receptor Antagonists - pharmacology Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - pharmacology Rats Receptors, Purinergic P2X7 - metabolism Science & Technology Stereoisomerism Tissue Distribution |
| Title | A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1H‑[1,2,3]triazolo[4,5‑c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate |
| URI | http://dx.doi.org/10.1021/acs.jmedchem.7b01279 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000422810800012 https://www.ncbi.nlm.nih.gov/pubmed/29211470 |
| Volume | 61 |
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