4 research outputs found
Challenges with the Synthesis of a Macrocyclic Thioether Peptide: From Milligram to Multigram Using Solid Phase Peptide Synthesis (SPPS)
We describe an optimization and scale-up of the 45-membered
macrocyclic
thioether peptide BMS-986189 utilizing solid-phase peptide synthesis
(SPPS). Improvements to linear peptide isolation, macrocyclization,
and peptide purification were demonstrated to increase the throughput
and purification of material on scale and enabled the synthesis and
purification of >60 g of target peptide. Taken together, not only
these improvements resulted in a 28-fold yield increase from the original
SPPS approach, but also the generality of this newly developed SPPS
purification sequence has found application in the synthesis and purification
of other macrocyclic thioether peptides
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 a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)
Factor XIa (FXIa)
is a blood coagulation enzyme that is involved
in the amplification of thrombin generation. Mounting evidence suggests
that direct inhibition of FXIa can block pathologic thrombus formation
while preserving normal hemostasis. Preclinical studies using a variety
of approaches to reduce FXIa activity, including direct inhibitors
of FXIa, have demonstrated good antithrombotic efficacy without increasing
bleeding. On the basis of this potential, we targeted our efforts
at identifying potent inhibitors of FXIa with a focus on discovering
an acute antithrombotic agent for use in a hospital setting. Herein
we describe the discovery of a potent FXIa clinical candidate, <b>55</b> (FXIa <i>K</i><sub>i</sub> = 0.7 nM), with excellent
preclinical efficacy in thrombosis models and aqueous solubility suitable
for intravenous administration. BMS-962212 is a reversible, direct,
and highly selective small molecule inhibitor of FXIa