7 research outputs found
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
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
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 key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. 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
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
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 key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. 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
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 (EC<sub>50</sub> <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 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
Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described.
This compound incorporates a cyclopropylÂacylsulfonamide moiety
that was designed to improve the potency of carboxylic acid prototypes
through the introduction of favorable nonbonding interactions within
the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties
including potency and pharmacokinetics (PK). This was achieved through
modulation of the P2* subsite of the inhibitor which identified the
isoquinoline ring system as a key template for improving PK properties
with further optimization achieved through functionalization. A methoxy
moiety at the C6 position of this isoquinoline ring system proved
to be optimal with respect to potency and PK, thus providing the clinical
compound <b>35</b> which demonstrated antiviral activity in
HCV-infected patients