DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors
| العنوان: | DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors |
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| المؤلفون: | Jonathan B. Basilla, Christopher P. Davie, Richard M. Dunham, Feng Wang, David Favre, Jeffrey A. Messer, Zhengrong Zhu, Bing Xia, Yoshiaki Washio, Alison Olszewski, Wieslaw M. Kazmierski, Lijun Fan, Makda Mebrahtu, Ghotas Evindar, Hongfeng Deng, Vicente Samano, Liping Wang, Martha Alicia De La Rosa, Ninad V. Prabhu, John F. Miller |
| المصدر: | Journal of Medicinal Chemistry. 63:3552-3562 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, In vivo, Drug Discovery, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Structure–activity relationship, Prodrugs, Spiro Compounds, Enzyme Inhibitors, Indoleamine 2,3-dioxygenase, 030304 developmental biology, Indole test, 0303 health sciences, Molecular Structure, Eutheria, Drug discovery, DNA, Prodrug, Combinatorial chemistry, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, Molecular Medicine |
| الوصف: | We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01799 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ce09a82de877db58e3932441b17f7c5 https://doi.org/10.1021/acs.jmedchem.9b01799 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....5ce09a82de877db58e3932441b17f7c5 |
| قاعدة البيانات: | OpenAIRE |
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