Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir

Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir

The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp2-hybridized hete...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 61; no. 14; pp. 6308 - 6327
Main Authors: Wang, Tao, Ueda, Yasu, Zhang, Zhongxing, Yin, Zhiwei, Matiskella, John, Pearce, Bradley C, Yang, Zheng, Zheng, Ming, Parker, Dawn D, Yamanaka, Gregory A, Gong, Yi-Fei, Ho, Hsu-Tso, Colonno, Richard J, Langley, David R, Lin, Pin-Fang, Meanwell, Nicholas A, Kadow, John F
Format: Journal Article
Language:English
Published: United States American Chemical Society 26-07-2018
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Summary:The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp2-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphono­oxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00759