6 research outputs found
Strategy to Improve the Quantitative LC-MS Analysis of Molecular Ions Resistant to Gas-Phase Collision Induced Dissociation: Application to Disulfide-Rich Cyclic Peptides
Due to observed collision induced
dissociation (CID) fragmentation
inefficiency, developing sensitive liquid chromatography tandem mass
spectrometry (LC-MS/MS) assays for CID resistant compounds is especially
challenging. As an alternative to traditional LC-MS/MS, we present
here a methodology that preserves the intact analyte ion for quantification
by selectively filtering ions while reducing chemical noise. Utilizing
a quadrupole-Orbitrap MS, the target ion is selectively isolated while
interfering matrix components undergo MS/MS fragmentation by CID,
allowing noise-free detection of the analyte’s surviving molecular
ion. In this manner, CID affords additional selectivity during high
resolution accurate mass analysis by elimination of isobaric interferences,
a fundamentally different concept than the traditional approach of
monitoring a target analyte’s unique fragment following CID.
This survivor-selected ion monitoring (survivor-SIM) approach has
allowed sensitive and specific detection of disulfide-rich cyclic
peptides extracted from plasma
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies
Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist
BMS-711939 (<b>3</b>) is a potent and selective peroxisome
proliferator-activated receptor (PPAR) α agonist, with an EC<sub>50</sub> of 4 nM for human PPARα and >1000-fold selectivity
vs human PPARγ (EC<sub>50</sub> = 4.5 μM) and PPARδ
(EC<sub>50</sub> > 100 μM) in PPAR-GAL4 transactivation assays.
Compound <b>3</b> also demonstrated excellent <i>in vivo</i> efficacy and safety profiles in preclinical studies and thus was
chosen for further preclinical evaluation. The synthesis, structure–activity
relationship (SAR) studies, and <i>in vivo</i> pharmacology
of <b>3</b> in preclinical animal models as well as its ADME
profile are described
Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
G protein-coupled
receptor 40 (GPR40) has become an attractive
target for the treatment of diabetes since it was shown clinically
to promote glucose-stimulated insulin secretion. Herein, we report
our efforts to develop highly selective and potent GPR40 agonists
with a dual mechanism of action, promoting both glucose-dependent
insulin and incretin secretion. Employing strategies to increase polarity
and the ratio of sp<sup>3</sup>/sp<sup>2</sup> character of the chemotype,
we identified BMS-986118 (compound <b>4</b>), which showed potent
and selective GPR40 agonist activity <i>in vitro</i>. <i>In vivo</i>, compound <b>4</b> demonstrated insulinotropic
efficacy and GLP-1 secretory effects resulting in improved glucose
control in acute animal models
Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
A novel series of pyrrolidine-containing
GPR40 agonists is described
as a potential treatment for type 2 diabetes. The initial pyrrolidine
hit was modified by moving the position of the carboxylic acid, a
key pharmacophore for GPR40. Addition of a 4-<i>cis</i>-CF<sub>3</sub> to the pyrrolidine improves the human GPR40 binding <i>K</i><sub>i</sub> and agonist efficacy. After further optimization,
the discovery of a minor enantiomeric impurity with agonist activity
led to the finding that enantiomers <b>(</b><i><b>R,R</b></i><b>)-68</b> and <b>(</b><i><b>S,S</b></i><b>)-68</b> have differential effects on the radioligand
used for the binding assay, with <b>(</b><i><b>R,R</b></i><b>)-68</b> potentiating the radioligand and <b>(</b><i><b>S,S</b></i><b>)-68</b> displacing
the radioligand. Compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> activates both
G<sub>q</sub>-coupled intracellular Ca<sup>2+</sup> flux and G<sub>s</sub>-coupled cAMP accumulation. This signaling bias results in
a dual mechanism of action for compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b>, demonstrating glucose-dependent insulin and GLP-1 secretion in
vitro. In vivo, compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> significantly lowers
plasma glucose levels in mice during an oral glucose challenge, encouraging
further development of the series