8 research outputs found
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]Âtriazol-1-yl-1<i>H</i>-pyrroloÂ[2,3-<i>c</i>]Âpyridin-3-yl)Âethane-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
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
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