GSK3532795 / BMS, ViiV Healthcare - LARVOL DELTA

Current status of the small molecule anti-HIV drugs in the pipeline or recently approved. (PubMed, Bioorg Med Chem) - "These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new..."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • CCR2

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation. (PubMed, J Med Chem) - "GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects."

Journal • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Exploration of phenyl isosteres in the context of HIV-1 maturation inhibitors (ACS-Fall 2021) - "As a result of these studies, several effective replacements for the phenyl ring of GSK3532795 were identified including a series of cyclohexenes and a novel spiro[3,3]hept-5-ene moiety that provide new vectors for substitution. These investigations ultimately led to the discovery of the next generation MI inhibitor GSK3640254 which is currently being evaluated in Phase IIb clinical trials."

Developmental Disorders • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] GSK3640254 IS A NOVEL MATURATION INHIBITOR WITH AN OPTIMIZED VIROLOGY PROFILE (CROI 2021) - "The antiviral activity of GSK'254 against select site-directed mutants (SDMs) was compared to a prior maturation inhibitor, GSK3532795 (GSK'795, formerly BMS-986176). These data demonstrate the optimized antiviral properties of GSK'254, a once-daily maturation inhibitor, against viruses with common MI-related gag polymorphisms. GSK'254 has been shown to provide significant reduction in viral load in people living with HIV in a phase 2A proof-of-concept study. Together, these data support the ongoing clinical development of GSK'254 in HIV-1 infected individuals"

Human Immunodeficiency Virus • Infectious Disease

Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition. (PubMed, Bioorg Med Chem Lett) - "This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage."

Journal • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Next generation HIV-1 maturation inhibitor: GSK3640254 (ACS-Fall 2020) - "GSK3640254, is a next generation HIV-1 maturation inhibitor that exhibits significantly improved pan-genotypic coverage and potency against polymorphic variants which exhibit reduced activity toward the second-generation MI GSK3532785 (BMS-955176). Key structural modifications to the C-3 position in the triterpenoid core of GSK3532785 provided a new vector to explore SAR which led to compounds with improved polymorphic coverage and PK properties. The design, synthetic route and preclinical profiles of GSK3640254 will be presented."

Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Next generation HIV-1 maturation inhibitor: GSK3640254 (ACS-Fall 2020) - "GSK3640254, is a next generation HIV-1 maturation inhibitor that exhibits significantly improved pan-genotypic coverage and potency against polymorphic variants which exhibit reduced activity toward the second-generation MI GSK3532785 (BMS-955176). Key structural modifications to the C-3 position in the triterpenoid core of GSK3532785 provided a new vector to explore SAR which led to compounds with improved polymorphic coverage and PK properties. The design, synthetic route and preclinical profiles of GSK3640254 will be presented."

Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Nontraditional benzoic acid surrogates: The design of spiro[3.3]hept-5-ene-2-carboxylic acid as a benzoic acid bioisostere and its application as an HIV-1 maturation inhibitor (ACS-Fall 2020) - "The recent discovery of GSK3532795 (formerly BMS-955176) as a second-generation HIV-1 maturation inhibitor that exhibits broad spectrum antiviral activity and preclinical PK predictive of once daily dosing demonstrates the potential of this class of antiviral agent...Unlike other traditional benzene replacements such as pyridine and acetylene, spiro[3.3]hept-5-ene allows for a modification of a second vector which could be helpful to probe SAR. To our knowledge, this is the first reporting of a spiro[3.3]hept-5-ene as a benzene replacement"

Human Immunodeficiency Virus • Infectious Disease

A Study to Determine the Effect of Multiple Doses of BMS-955176 on the Electrocardiograph of Healthy Subjects (clinicaltrials.gov) - P1; N=315; Terminated; Sponsor: ViiV Healthcare; Withdrawn ➔ Terminated; This study was terminated early due to neuropsychiatric serious adverse events reported by 2 participants.

Trial termination • Biosimilar • Gene Therapies • Human Immunodeficiency Virus • Immunology • Infectious Disease

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study. (PubMed, PLoS One) - "GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection...H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants."

Journal

Spiro[3.3]hept-5-ene-2-carboxylic acid as a benzoic acid bioisostere: Design and application of a novel benzoic acid replacement as an HIV-1 maturation inhibitor (ACS-Sp 2020) - "The recent discovery of GSK3532795 (formerly BMS-955176) as a second-generation HIV-1 maturation inhibitor has shown broad spectrum antiviral activity and preclinical PK predictive of once daily dosing can be achieved...Unlike other traditional benzene replacements such as pyridine and acetylene, spiro[3.3]hept-5-ene allows for a modification of a second vector which could be helpful to probe SAR. To our knowledge, this is the first reporting of a spiro[3.3]hept-5-ene as a benzene replacement."

Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-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 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795,... (PubMed, J Med Chem) - "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 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC <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."

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Second Generation Inhibitors of HIV-1 Maturation. (PubMed, ACS Med Chem Lett) - "The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described."

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