Discovery of TRPA1 Antagonist GDC-6599 : Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3287-3306 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Terrett, Jack A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Aldehyde Oxidase |
|---|
| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.3c02121 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369217136 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369217136 | ||
| 003 | DE-627 | ||
| 005 | 20240315233507.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240304s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.3c02121 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1330.xml |
| 035 | |a (DE-627)NLM369217136 | ||
| 035 | |a (NLM)38431835 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Terrett, Jack A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of TRPA1 Antagonist GDC-6599 |b Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.03.2024 | ||
| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Transient Receptor Potential Channels |2 NLM | |
| 650 | 7 | |a TRPA1 Cation Channel |2 NLM | |
| 650 | 7 | |a Aldehyde Oxidase |2 NLM | |
| 650 | 7 | |a EC 1.2.3.1 |2 NLM | |
| 650 | 7 | |a Oxidoreductases |2 NLM | |
| 650 | 7 | |a EC 1.- |2 NLM | |
| 650 | 7 | |a Cytoskeletal Proteins |2 NLM | |
| 650 | 7 | |a TRPA1 protein, human |2 NLM | |
| 700 | 1 | |a Ly, Justin Q |e verfasserin |4 aut | |
| 700 | 1 | |a Katavolos, Paula |e verfasserin |4 aut | |
| 700 | 1 | |a Hasselgren, Catrin |e verfasserin |4 aut | |
| 700 | 1 | |a Laing, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Fiona |e verfasserin |4 aut | |
| 700 | 1 | |a Villemure, Elisia |e verfasserin |4 aut | |
| 700 | 1 | |a Déry, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Larouche-Gauthier, Robin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Huifen |e verfasserin |4 aut | |
| 700 | 1 | |a Shore, Daniel G |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Wyne P |e verfasserin |4 aut | |
| 700 | 1 | |a Suto, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Brooks, Marjory |e verfasserin |4 aut | |
| 700 | 1 | |a Stablein, Alyssa |e verfasserin |4 aut | |
| 700 | 1 | |a Beaumier, Francis |e verfasserin |4 aut | |
| 700 | 1 | |a Constantineau-Forget, Léa |e verfasserin |4 aut | |
| 700 | 1 | |a Grand-Maître, Chantal |e verfasserin |4 aut | |
| 700 | 1 | |a Lépissier, Luce |e verfasserin |4 aut | |
| 700 | 1 | |a Ciblat, Stéphane |e verfasserin |4 aut | |
| 700 | 1 | |a Sturino, Claudio |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Baihua |e verfasserin |4 aut | |
| 700 | 1 | |a Elstrott, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Gandham, Vineela |e verfasserin |4 aut | |
| 700 | 1 | |a Joseph, Victory |e verfasserin |4 aut | |
| 700 | 1 | |a Booler, Helen |e verfasserin |4 aut | |
| 700 | 1 | |a Cain, Gary |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Carolina |e verfasserin |4 aut | |
| 700 | 1 | |a Fullerton, Aaron |e verfasserin |4 aut | |
| 700 | 1 | |a Lepherd, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Stainton, Shannon |e verfasserin |4 aut | |
| 700 | 1 | |a Torres, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Urban, Konnie |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Lanlan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Bao, Linda |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Kang-Jye |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a La, Hank |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Liling |e verfasserin |4 aut | |
| 700 | 1 | |a Mulder, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Chernov-Rogan, Tania |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Adam R |e verfasserin |4 aut | |
| 700 | 1 | |a Hackos, David H |e verfasserin |4 aut | |
| 700 | 1 | |a Leahey, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Shields, Shannon D |e verfasserin |4 aut | |
| 700 | 1 | |a Balestrini, Alessia |e verfasserin |4 aut | |
| 700 | 1 | |a Riol-Blanco, Lorena |e verfasserin |4 aut | |
| 700 | 1 | |a Safina, Brian S |e verfasserin |4 aut | |
| 700 | 1 | |a Volgraf, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Magnuson, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Kakiuchi-Kiyota, Satoko |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 5 vom: 14. März, Seite 3287-3306 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:67 |g year:2024 |g number:5 |g day:14 |g month:03 |g pages:3287-3306 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.3c02121 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 67 |j 2024 |e 5 |b 14 |c 03 |h 3287-3306 | ||