13 research outputs found
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs.
Two chemotypes were examined in vitro with CYPs 3A4 and 2C19 by molecular docking, metabolic profiles, and intrinsic clearance deuterium isotope effects with specifically deuterated form to assess the potential for enhancement of pharmacokinetic parameters. The results show the complexity of deuteration as an approach for pharmacokinetic enhancement when CYP enzymes are involved in metabolic clearance. With CYP3A4 the rate limiting step was chemotype-dependent. With one chemotype no intrinsic clearance deuterium isotope effect was observed with any deuterated form, whereas with the other chemotype the rate limiting step was isotopically sensitive, and the magnitude of the intrinsic clearance isotope effect was dependent on the position(s) and extent of deuteration. Molecular docking and metabolic profiles aided in identifying sites for deuteration and predicted the possibility for metabolic switching. However, the potential for an isotope effect on the intrinsic clearance cannot be predicted and must be established by examining select deuterated versions of the chemotypes. The results show how in a deuteration strategy molecular docking, in-vitro metabolic profiles, and intrinsic clearance assessments with select deuterated versions of new chemical entities can be applied to determine the potential for pharmacokinetic enhancement in a discovery setting. They also help explain the substantial failures reported in the literature of deuterated versions of drugs to elicit a systemic enhancement on pharmacokinetic parameters
Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
https://researchrepository.wvu.edu/wvu_herbwvfern/2465/thumbnail.jp
Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists
Several polar heteroaromatic acetic
acids and their piperidine
amides were synthesized and evaluated as ghrelin or type 1a growth
hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts
to improve pharmacokinetic and safety profile was achieved by modulating
physicochemical properties and, more specifically, emphasizing increased
polarity of our chemical series. <i>ortho</i>-Carboxamide
containing compounds provided optimal physicochemical, pharmacologic,
and safety profile. pH-dependent chemical stability was also assessed
with our series
Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
The identification of potent, highly
selective orally bioavailable
ghrelin receptor inverse agonists from a spiro-azetidino-piperidine
series is described. Examples from this series have promising in vivo
pharmacokinetics and increase glucose-stimulated insulin secretion
in human whole and dispersed islets. A physicochemistry-based strategy
to increase lipophilic efficiency for ghrelin receptor potency and
retain low clearance and satisfactory permeability while reducing
off-target pharmacology led to the discovery of <b>16h</b>.
Compound <b>16h</b> has a superior balance of ghrelin receptor
pharmacology and off-target selectivity. On the basis of its promising
pharmacological and safety profile, <b>16h</b> was advanced
to human clinical trials
Identification of Tetrahydropyrido[4,3â<i>d</i>]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists
Takeda G-protein-coupled receptor 5 (TGR5) represents
an exciting
biological target for the potential treatment of diabetes and metabolic
syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyridoÂ[4,3-<i>d</i>]Âpyrimidine amide TGR5 agonists is disclosed. We describe
our effort to identify an orally available agonist suitable for assessment
of systemic TGR5 agonism. This effort resulted in identification of <b>16</b>, which had acceptable potency and pharmacokinetic properties
to allow for in vivo assessment in dog. A key aspect of this work
was the calibration of human and dog in vitro assay systems that could
be linked with data from a human ex vivo peripheral blood monocyte
assay that expresses receptor at endogenous levels. Potency from the
human in vitro assay was also found to correlate with data from an
ex vivo human whole blood assay. This calibration exercise provided
confidence that <b>16</b> could be used to drive plasma exposures
sufficient to test the effects of systemic activation of TGR5
Discovery of an <i>in Vivo</i> Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment
Recent studies in adipose tissue,
pancreas, muscle, and macrophages
suggest that MAP4K4, a serine/threonine protein kinase may be a viable
target for antidiabetic drugs. As part of the evaluation of MAP4K4
as a novel antidiabetic target, a tool compound, <b>16</b> (PF-6260933)
and a lead <b>17</b> possessing excellent kinome selectivity
and suitable properties were delivered to establish proof of concept <i>in vivo</i>. The medicinal chemistry effort that led to the
discovery of these lead compounds is described herein together with <i>in vivo</i> pharmacokinetic properties and activity in a model
of insulin resistance