5 research outputs found
Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products
A thermodynamic approach to peptide
macrocyclization inspired by
the cyclization of non-ribosomal peptide aldehydes is presented. The
method provides access to structurally diverse macrocycles by exploiting
the reactivity of transient macrocyclic peptide imines toward inter-
and intramolecular nucleophiles. Reactions are performed in aqueous
media, in the absence of side chain protecting groups, and are tolerant
of all proteinogenic functional groups. Macrocyclic products bearing
non-native and rigidifying structural motifs, isotopic labels, and
a variety of bioorthogonal handles are prepared, along with analogues
of four distinct natural products. Structural interrogation of the
linear and macrocyclic peptides using variable-temperature NMR and
circular dichroism suggests that preorganization of linear substrates
is not a prerequisite for macrocyclization
Ligand-Enabled β‑C–H Arylation of α‑Amino Acids Using a Simple and Practical Auxiliary
Pd-catalyzed β-C–H functionalizations
of carboxylic
acid derivatives using an auxiliary as a directing group have been
extensively explored in the past decade. In comparison to the most
widely used auxiliaries in asymmetric synthesis, the simplicity and
practicality of the auxiliaries developed for C–H activation
remains to be improved. We previously developed a simple <i>N</i>-methoxyamide auxiliary to direct β-C–H activation,
albeit this system was not compatible with carboxylic acids containing
α-hydrogen atoms. Herein we report the development of a pyridine-type
ligand that overcomes this limitation of the <i>N</i>-methoxyamide
auxiliary, leading to a significant improvement of β-arylation
of carboxylic acid derivatives, especially α-amino acids. The
arylation using this practical auxiliary is applied to the gram-scale
syntheses of unnatural amino acids, bioactive molecules, and chiral
bisÂ(oxazoline) ligands
Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor
The
design and synthesis of potent, tripeptidic acylsulfonamide
inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl
amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond
between the polarized C–H of the CHF<sub>2</sub> moiety and
the backbone carbonyl of Leu135 of the enzyme. Structure–activity
relationship studies indicate that this H-bond enhances enzyme inhibitory
potency by 13- and 17-fold compared to the CH<sub>3</sub> and CF<sub>3</sub> analogues, respectively, providing insight into the deployment
of this unique amino acid
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
Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing
The
discovery of a back-up to the hepatitis C virus NS3 protease inhibitor
asunaprevir (<b>2</b>) is described. The objective of this work
was the identification of a drug with antiviral properties and toxicology
parameters similar to <b>2</b>, but with a preclinical pharmacokinetic
(PK) profile that was predictive of once-daily dosing. Critical to
this discovery process was the employment of an ex vivo cardiovascular
(CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation
of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity
relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications
at the P1 site, while potency gains were found with small, but rationally
designed structural changes to P4. Additional modifications at P3
were required to optimize the CV profile, and these combined SARs
led to the discovery of BMS-890068 (<b>29</b>)