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

  • J Med Chem. 2018 Jul 26;61(14):6308-6327. doi: 10.1021/acs.jmedchem.8b00759.
Tao Wang ,  Yasu Ueda ,  Zhongxing Zhang ,  Zhiwei Yin ,  John Matiskella ,  Bradley C Pearce ,  Zheng Yang ,  Ming Zheng ,  Dawn D Parker ,  Gregory A Yamanaka ,  Yi-Fei Gong ,  Hsu-Tso Ho ,  Richard J Colonno ,  David R Langley ,  Pin-Fang Lin ,  Nicholas A Meanwell ,  John F Kadow
PMID: 29920093 DOI: 10.1021/acs.jmedchem.8b00759
Abstract

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.