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 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.

Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects.

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.

Severe acute respiratory syndrome coronavirus entry into host cells: Opportunities for therapeutic intervention.

A novel human coronavirus (CoV) has been identified as the etiological agent that caused the severe acute respiratory syndrome (SARS) outbreak in 2003. The spike (S) protein of this virus is a type I surface glycoprotein that mediates binding of the virus to the host receptor and the subsequent fusion between the viral and host membranes. Because of its critical role in viral entry, the S protein is an important target for the development of anti-SARS CoV therapeutics and prophylactics. This article reviews the structure and function of the SARS CoV S protein in the context of its role in virus entry. Topics that are discussed include: the interaction between the S1 domain of the SARS spike protein and the cellular receptor, angiotensin converting enzyme 2 (ACE2), and the structural features of the ectodomain of ACE2; the antigenic determinants presented by the S protein and the nature of neutralizing monoclonal antibodies that are elicited in vivo; the structure of the 4,3-hydrophobic heptad repeats HR1 and HR2 of the S2 domain and their interaction to form a six-helical bundle during the final stages of fusion. Opportunities for the design and development of anti-SARS agents based on the inhibition of receptor binding, the therapeutic uses of S-directed monoclonal antibodies and inhibitors of HR1-HR2 complex formation are presented.