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 <b>1</b> to deliver temsavir (<b>3</b>, 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 <b>3</b> with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of <b>3</b> 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 <b>4</b> (BMS-663068, fostemsavir). An extended-release formulation of <b>4</b> 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. 12. Structure–Activity Relationships Associated with 4‑Fluoro-6-azaindole Derivatives Leading to the Identification of 1‑(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl‑1<i>H</i>‑pyrrolo[2,3‑<i>c</i>]pyridin-3-yl)ethane-1,2-dione (BMS-585248)

A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (<b>12a</b>,<b>b</b>), C-linked heterocycles (<b>12c</b>–<b>l</b>), and N-linked heterocycles (<b>12m</b>–<b>u</b>) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]­triazol-1-yl-1<i>H</i>-pyrrolo­[2,3-<i>c</i>]­pyridin-3-yl)­ethane-1,2-dione (BMS-585248, <b>12m</b>) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (<b>1</b>). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for <b>12m</b> led to its selection for human clinical studies

Potent Long-Acting Inhibitors Targeting the HIV‑1 Capsid Based on a Versatile Quinazolin-4-one Scaffold

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug–drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs

Potent Long-Acting Inhibitors Targeting the HIV‑1 Capsid Based on a Versatile Quinazolin-4-one Scaffold

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug–drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs

Discovery of BMS-955176, a Second Generation HIV‑1 Maturation Inhibitor with Broad Spectrum Antiviral Activity

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (<b>2</b>), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen

Design, Synthesis, and SAR of C‑3 Benzoic Acid, C‑17 Triterpenoid Derivatives. Identification of the HIV‑1 Maturation Inhibitor 4‑((1<i>R</i>,3a<i>S</i>,5a<i>R</i>,5b<i>R</i>,7a<i>R</i>,11a<i>S</i>,11b<i>R</i>,13a<i>R</i>,13b<i>R</i>)‑3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro‑1<i>H</i>‑cyclopenta[<i>a</i>]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)

GSK3532795, formerly known as BMS-955176 (<b>1</b>), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (<b>3</b>) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure–activity relationships (SARs) that led to the design of the specific C-17 amine moiety in <b>1</b>. These modifications ultimately enabled the discovery of <b>1</b> as a second-generation MI that combines broad coverage of polymorphic viruses (EC₅₀ <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase

Described herein are structure–activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (<b>2</b>) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation