446289-94-7Relevant articles and documents
Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir
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.
, p. 6308 - 6327 (2018/06/27)
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.