52 research outputs found
Diagnosis of prostate cancer with magnetic resonance imaging in men treated with 5-alpha-reductase inhibitors
Purpose The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade >= 2).Methods This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients.Results 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naive (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p < 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG >= 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS >= 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively.Conclusions Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions.Trial registration The present study was registered at ClinicalTrials.gov number: NCT05078359
Symmetric Kv1.5 Blockers Discovered by Focused Screening
Guided by computational methods, a set of 1920 compounds
were selected
from the AstraZeneca corporate collection and screened for Kv1.5 activity.
To facilitate rapid generation of structureāactivity relationships,
special attention was given to selecting subsets of structurally similar
molecules by using a maximum common substructure similarity-based
procedure. The focused screen hit rate was relatively high (12%).
More importantly, a structural series featured by the symmetric 1,2-diphenylethane-1,2-diamine
substructure was identified as potent Kv.1.5 blockers. The property
profile for the series is shown to meet stringent lead-optimization
criteria, providing a springboard for the development of a new and
safe treatment for atrial fibrillation
Introducing Uncertainty in Predictive ModelingīøFriend or Foe?
Uncertainty was introduced to chemical descriptors of
16 publicly available data sets to various degrees and in various
ways in order to investigate the effect on the predictive performance
of the state-of-the-art method decision tree ensembles. A number of
strategies to handle uncertainty in decision tree ensembles were evaluated.
The main conclusion of the study is that uncertainty to a large extent
may be introduced in chemical descriptors without impairing the predictive
performance of ensembles and without the predictive performance being
significantly reduced from a practical point of view. The investigation
further showed that even when distributions of uncertain values were
provided, the ensembles method could generate equally effective models
from single-point samples from these distributions. Hence, there seems
to be no advantage in using more elaborate methods for handling uncertainty
in chemical descriptors when using decision tree ensembles as a modeling
method for the considered types of introduced uncertainty
Introducing Uncertainty in Predictive ModelingīøFriend or Foe?
Uncertainty was introduced to chemical descriptors of
16 publicly available data sets to various degrees and in various
ways in order to investigate the effect on the predictive performance
of the state-of-the-art method decision tree ensembles. A number of
strategies to handle uncertainty in decision tree ensembles were evaluated.
The main conclusion of the study is that uncertainty to a large extent
may be introduced in chemical descriptors without impairing the predictive
performance of ensembles and without the predictive performance being
significantly reduced from a practical point of view. The investigation
further showed that even when distributions of uncertain values were
provided, the ensembles method could generate equally effective models
from single-point samples from these distributions. Hence, there seems
to be no advantage in using more elaborate methods for handling uncertainty
in chemical descriptors when using decision tree ensembles as a modeling
method for the considered types of introduced uncertainty
Where Do Recent Small Molecule Clinical Development Candidates Come From?
An
analysis of 66 published clinical candidates from <i>Journal
of Medicinal Chemistry</i> has been conducted to shed light on
which lead generation strategies are most frequently employed in identifying
drug candidates. The most frequent lead generation strategy (producing
a drug candidate) was based on starting points derived from previously
known compounds (43%) followed by random high throughput screening
(29%). The remainder of approaches included focused screening, structure-based
drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded
library screening (DEL). An analysis of physicochemical properties
on the hit-to-clinical pairs shows an average increase in molecular
weight (ĪMW = +85) but no change in lipophilicity (ĪclogP
= ā0.2), although exceptions are noted. The majority (>50%)
of clinical candidates were found to be structurally very different
from their starting point and were more complex. Finally, several
reports of noncovalent scaffolds modified by a covalent warhead using
SBDD approaches are discussed
Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
An analysis of chemical reactions
used in current medicinal chemistry
(2014), three decades ago (1984), and in natural product total synthesis
has been conducted. The analysis revealed that of the current most
frequently used synthetic reactions, none were discovered within the
past 20 years and only two in the 1980s and 1990s (SuzukiāMiyaura
and BuchwaldāHartwig). This suggests an inherent high bar of
impact for new synthetic reactions in drug discovery. The most frequently
used reactions were amide bond formation, SuzukiāMiyaura coupling,
and S<sub>N</sub>Ar reactions, most likely due to commercial availability
of reagents, high chemoselectivity, and a pressure on delivery. We
show that these practices result in overpopulation of certain types
of molecular shapes to the exclusion of others using simple PMI plots.
We hope that these results will help catalyze improvements in integration
of new synthetic methodologies as well as new library design
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