14 research outputs found
Secalonic Acid D Alters the Nature of and Inhibits the Binding of the Transcription Factors to the Phorbol 12-O-Tetradecanoate-13 Acetate-Response Element in the Developing Murine Secondary Palate
Systemic Loss of C-terminal Src Kinase Expression Elicits Spontaneous Suppurative Inflammation in Conditional Knockout Mice
Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase
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 design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation
Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor
Iterative structure–activity
analyses in a class of highly
functionalized furoÂ[2,3-<i>b</i>]Âpyridines led to the identification
of the second generation pan-genotypic hepatitis C virus NS5B polymerase
primer grip inhibitor BMT-052 (<b>14</b>), a potential clinical
candidate. The key challenge of poor metabolic stability was overcome
by strategic incorporation of deuterium at potential metabolic soft
spots. The preclinical profile and status of BMT-052 (<b>14</b>) is described
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
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