4 research outputs found
Chemoselective Peptide Modification via Photocatalytic Tryptophan β‑Position Conjugation
Targeting tryptophan
is a promising strategy to achieve high levels
of selectivity for peptide or protein modification. A chemoselective
peptide modification method via photocatalytic tryptophan β-position
conjugation has been discovered. This transformation has good substrate
scope for both peptide and Michael acceptor, and has good chemoselectivity
versus other amino acid residues. The endogenous peptides, glucagon
and GLP-1 amide, were both successfully conjugated at the tryptophan
β-position. Insulin was studied as a nontryptophan control molecule,
resulting in exclusive B-chain C-terminal-selective decarboxylative
conjugation. This transformation provides a novel approach toward
peptide modification to support the discovery of new therapeutic peptides,
protein labeling and bioconjugation
Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia
Structure-guided optimization of a series of C-5 alkyl
substituents
led to the discovery of a potent nicotinic acid receptor agonist SCH
900271 (<b>33</b>) with an EC<sub>50</sub> of 2 nM in the hu-GPR109a
assay. Compound <b>33</b> demonstrated good oral bioavailability
in all species. Compound <b>33</b> exhibited dose-dependent
inhibition of plasma free fatty acid (FFA) with 50% FFA reduction
at 1.0 mg/kg in fasted male beagle dogs. Compound <b>33</b> had
no overt signs of flushing at doses up to 10 mg/kg with an improved
therapeutic window to flushing as compared to nicotinic acid. Compound <b>33</b> was evaluated in human clinical trials
Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration
The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates
Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration
The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates