17 research outputs found
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Discovery and Lead Optimization of a Novel Series of CC Chemokine Receptor 1 (CCR1)-Selective Piperidine Antagonists via Parallel Synthesis
A series of novel, potent CCR1 inhibitors was developed
from a
moderately active hit using an iterative parallel synthesis approach.
The initial hit (composed of three subunits: an amine, a central amino
acid, and an N-terminal cap) became the basis for a series of parallel
chemical libraries designed to generate SAR data. Libraries were synthesized
that explored each of the three subunits; the CCR1 binding data obtained
revealed the following: (1) changes to the amine are not well tolerated;
(2) small alkylamino acids are preferred in the center of the molecule;
(3) substitutions at the N-terminus are generally well tolerated.
These data were used to drive the optimization of the series, ultimately
providing a lead with a CCR1 binding IC<sub>50</sub> of 28 nM (<b>48</b>). This lead demonstrates high selectivity for CCR1 over
other CCR-family members, high microsomal stability, and good pharmacokinetics
in mice
Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5
We
describe the hybridization of our previously reported acyclic
and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a
new series of dual antagonists of CCR2 and CCR5. Installation of a
γ-lactam as the spacer group and a quinazoline as a benzamide
mimetic improved oral bioavailability markedly. These efforts led
to the identification of <b>13d</b>, a potent and orally bioavailable
dual antagonist suitable for use in both murine and monkey models
of inflammation
Impact of diabetes on remodelling, microvascular function and exercise capacity in aortic stenosis
Objective To characterise cardiac remodelling, exercise capacity and fibroinflammatory biomarkers in patients with aortic stenosis (AS) with and without diabetes, and assess the impact of diabetes on outcomes.
Methods Patients with moderate or severe AS with and without diabetes underwent echocardiography, stress cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing and plasma biomarker analysis. Primary endpoint for survival analysis was a composite of cardiovascular mortality, myocardial infarction, hospitalisation with heart failure, syncope or arrhythmia. Secondary endpoint was all-cause death.
Results Diabetes (n=56) and non-diabetes groups (n=198) were well matched for age, sex, ethnicity, blood pressure and severity of AS. The diabetes group had higher body mass index, lower estimated glomerular filtration rate and higher rates of hypertension, hyperlipidaemia and symptoms of AS. Biventricular volumes and systolic function were similar, but the diabetes group had higher extracellular volume fraction (25.9%±3.1% vs 24.8%±2.4%, p=0.020), lower myocardial perfusion reserve (2.02±0.75 vs 2.34±0.68, p=0.046) and lower percentage predicted peak oxygen consumption (68%±21% vs 77%±17%, p=0.002) compared with the non-diabetes group. Higher levels of renin (log10renin: 3.27±0.59 vs 2.82±0.69 pg/mL, p
Conclusions In patients with moderate-to-severe AS, diabetes is associated with reduced exercise capacity, increased diffuse myocardial fibrosis and microvascular dysfunction, but not cardiovascular events despite a small increase in mortality.</p
Is atrial fibrillation in HFpEF a distinct phenotype? Insights from multiparametric MRI and circulating biomarkers.
Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently co-exist. There is a limited understanding on whether this coexistence is associated with distinct alterations in myocardial remodelling and mechanics. We aimed to determine if patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) represent a distinct phenotype.In this secondary analysis of adults with HFpEF (NCT03050593), participants were comprehensively phenotyped with stress cardiac MRI, echocardiography and plasma fibroinflammatory biomarkers, and were followed for the composite endpoint (HF hospitalisation or death) at a median of 8.5 years. Those with AF were compared to sinus rhythm (SR) and unsupervised cluster analysis was performed to explore possible phenotypes.136 subjects were included (SR = 75, AF = 61). The AF group was older (76 ± 8 vs. 70 ± 10 years) with less diabetes (36% vs. 61%) compared to the SR group and had higher left atrial (LA) volumes (61 ± 30 vs. 39 ± 15 mL/m2, p 
Background
Methods
Results
Conclusions</p
Is atrial fibrillation in HFpEF a distinct phenotype? Insights from multiparametric MRI and circulating biomarkers.
Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently co-exist. There is a limited understanding on whether this coexistence is associated with distinct alterations in myocardial remodelling and mechanics. We aimed to determine if patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) represent a distinct phenotype.In this secondary analysis of adults with HFpEF (NCT03050593), participants were comprehensively phenotyped with stress cardiac MRI, echocardiography and plasma fibroinflammatory biomarkers, and were followed for the composite endpoint (HF hospitalisation or death) at a median of 8.5 years. Those with AF were compared to sinus rhythm (SR) and unsupervised cluster analysis was performed to explore possible phenotypes.136 subjects were included (SR = 75, AF = 61). The AF group was older (76 ± 8 vs. 70 ± 10 years) with less diabetes (36% vs. 61%) compared to the SR group and had higher left atrial (LA) volumes (61 ± 30 vs. 39 ± 15 mL/m2, p 
Background
Methods
Results
Conclusions</p
Potent and Selective Agonists of Sphingosine 1‑Phosphate 1 (S1P<sub>1</sub>): Discovery and SAR of a Novel Isoxazole Based Series
Sphingosine 1-phosphate (S1P) is
the endogenous ligand for the
sphingosine 1-phosphate receptors (S1P<sub>1–5</sub>) and evokes
a variety of cellular responses through their stimulation. The interaction
of S1P with the S1P receptors plays a fundamental physiological role
in a number of processes including vascular development and stabilization,
lymphocyte migration, and proliferation. Agonism of S1P<sub>1</sub>, in particular, has been shown to play a significant role in lymphocyte
trafficking from the thymus and secondary lymphoid organs, resulting
in immunosuppression. This article will detail the discovery and SAR
of a potent and selective series of isoxazole based full agonists
of S1P<sub>1</sub>. Isoxazole <b>6d</b> demonstrated impressive
efficacy when administered orally in a rat model of arthritis and
in a mouse experimental autoimmune encephalomyelitis (EAE) model of
multiple sclerosis