12 research outputs found
The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.
Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation
Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres
The total optimal search criterion in solving the mixed integer linear model with GNSS carrier phase observations
The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging
As
part of our effort in identifying phosphodiesterase (PDE) 4B-preferring
inhibitors for the treatment of central nervous system (CNS) disorders,
we sought to identify a positron emission tomography (PET) ligand
to enable target occupancy measurement in vivo. Through a systematic
and cost-effective PET discovery process, involving expression level
(<i>B</i><sub>max</sub>) and biodistribution determination,
a PET-specific structure–activity relationship (SAR) effort,
and specific binding assessment using a LC-MS/MS “cold tracer”
method, we have identified <b>8</b> (PF-06445974) as a promising
PET lead. Compound <b>8</b> has exquisite potency at PDE4B,
good selectivity over PDE4D, excellent brain permeability, and a high
level of specific binding in the “cold tracer” study.
In subsequent non-human primate (NHP) PET imaging studies, [<sup>18</sup>F]<b>8</b> showed rapid brain uptake and high target specificity,
indicating that [<sup>18</sup>F]<b>8</b> is a promising PDE4B-preferring
radioligand for clinical PET imaging
The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging
As
part of our effort in identifying phosphodiesterase (PDE) 4B-preferring
inhibitors for the treatment of central nervous system (CNS) disorders,
we sought to identify a positron emission tomography (PET) ligand
to enable target occupancy measurement in vivo. Through a systematic
and cost-effective PET discovery process, involving expression level
(<i>B</i><sub>max</sub>) and biodistribution determination,
a PET-specific structure–activity relationship (SAR) effort,
and specific binding assessment using a LC-MS/MS “cold tracer”
method, we have identified <b>8</b> (PF-06445974) as a promising
PET lead. Compound <b>8</b> has exquisite potency at PDE4B,
good selectivity over PDE4D, excellent brain permeability, and a high
level of specific binding in the “cold tracer” study.
In subsequent non-human primate (NHP) PET imaging studies, [<sup>18</sup>F]<b>8</b> showed rapid brain uptake and high target specificity,
indicating that [<sup>18</sup>F]<b>8</b> is a promising PDE4B-preferring
radioligand for clinical PET imaging
Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)
Increased
fructose consumption and its subsequent metabolism have
been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin
resistance in humans. Since ketohexokinase (KHK) is the principal
enzyme responsible for fructose metabolism, identification of a selective
KHK inhibitor may help to further elucidate the effect of KHK inhibition
on these metabolic disorders. Until now, studies on KHK inhibition
with small molecules have been limited due to the lack of viable in
vivo pharmacological tools. Herein we report the discovery of <b>12</b>, a selective KHK inhibitor with potency and properties
suitable for evaluating KHK inhibition in rat models. Key structural
features interacting with KHK were discovered through fragment-based
screening and subsequent optimization using structure-based drug design,
and parallel medicinal chemistry led to the identification of pyridine <b>12</b>
Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation
A major challenge
in the development of β-site amyloid precursor
protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of
Alzheimer’s disease is the alignment of potency, drug-like
properties, and selectivity over related aspartyl proteases such as
Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting
BACE2 chronically have only recently begun to emerge as BACE2 impacts
the processing of the premelanosome protein (PMEL17) and disrupts
melanosome morphology resulting in a depigmentation phenotype. Herein,
we describe the identification of clinical candidate PF-06751979 (<b>64</b>), which displays excellent brain penetration, potent in
vivo efficacy, and broad selectivity over related aspartyl proteases
including BACE2. Chronic dosing of <b>64</b> for up to 9 months
in dog did not reveal any observation of hair coat color (pigmentation)
changes and suggests a key differentiator over current BACE1 inhibitors
that are nonselective against BACE2 in later stage clinical development
Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation
A major challenge
in the development of β-site amyloid precursor
protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of
Alzheimer’s disease is the alignment of potency, drug-like
properties, and selectivity over related aspartyl proteases such as
Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting
BACE2 chronically have only recently begun to emerge as BACE2 impacts
the processing of the premelanosome protein (PMEL17) and disrupts
melanosome morphology resulting in a depigmentation phenotype. Herein,
we describe the identification of clinical candidate PF-06751979 (<b>64</b>), which displays excellent brain penetration, potent in
vivo efficacy, and broad selectivity over related aspartyl proteases
including BACE2. Chronic dosing of <b>64</b> for up to 9 months
in dog did not reveal any observation of hair coat color (pigmentation)
changes and suggests a key differentiator over current BACE1 inhibitors
that are nonselective against BACE2 in later stage clinical development
Événement d'art vidéo 90-91 : Événement inter-universitaire 1er cycle de l'art vidéo
Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors
In recent years, the first generation
of β-secretase (BACE1)
inhibitors advanced into clinical development for the treatment of
Alzheimer’s disease (AD). However, the alignment of drug-like
properties and selectivity remains a major challenge. Herein, we describe
the discovery of a novel class of potent, low clearance, CNS penetrant
BACE1 inhibitors represented by thioamidine <b>5</b>. Further
profiling suggested that a high fraction of the metabolism (>95%)
was due to CYP2D6, increasing the potential risk for victim-based
drug–drug interactions (DDI) and variable exposure in the clinic
due to the polymorphic nature of this enzyme. To guide future design,
we solved crystal structures of CYP2D6 complexes with substrate <b>5</b> and its corresponding metabolic product pyrazole <b>6</b>, which provided insight into the binding mode and movements between
substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal
structures, we designed and synthesized analogues with reduced risk
for DDI, central efficacy, and improved hERG therapeutic margins