Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis : Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors
© 2021 American Chemical Society..
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
ACS medicinal chemistry letters - 12(2021), 3 vom: 11. März, Seite 389-396 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Derun [VerfasserIn] |
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| Anmerkungen: |
Date Revised 31.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/acsmedchemlett.0c00525 |
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| Förderinstitution / Projekttitel: |
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NLM322945585 |
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| 245 | 1 | 0 | |a Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis |b Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors |
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| 520 | |a © 2021 American Chemical Society. | ||
| 520 | |a Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans | ||
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| 700 | 1 | |a Achab, Abdelghani |e verfasserin |4 aut | |
| 700 | 1 | |a Bharathan, Indu |e verfasserin |4 aut | |
| 700 | 1 | |a Hopkins, Brett Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Wensheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hongjun |e verfasserin |4 aut | |
| 700 | 1 | |a Sanyal, Sulagna |e verfasserin |4 aut | |
| 700 | 1 | |a Pu, Qinglin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Jongwon |e verfasserin |4 aut | |
| 700 | 1 | |a Fradera, Xavier |e verfasserin |4 aut | |
| 700 | 1 | |a Lesburg, Charles A |e verfasserin |4 aut | |
| 700 | 1 | |a Lammens, Alfred |e verfasserin |4 aut | |
| 700 | 1 | |a Martinot, Theodore A |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Ryan D |e verfasserin |4 aut | |
| 700 | 1 | |a Doty, Amy C |e verfasserin |4 aut | |
| 700 | 1 | |a Ferguson, Heidi |e verfasserin |4 aut | |
| 700 | 1 | |a Nickbarg, Elliott B |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Mangeng |e verfasserin |4 aut | |
| 700 | 1 | |a Spacciapoli, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Geda, Prasanthi |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Xuelei |e verfasserin |4 aut | |
| 700 | 1 | |a Smotrov, Nadya |e verfasserin |4 aut | |
| 700 | 1 | |a Abeywickrema, Pravien |e verfasserin |4 aut | |
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