A5038500101- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Drug Transport and Resistance Mechanisms
- Drug Solubulity and Delivery Systems
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Pharmacogenetics and Drug Metabolism
- Analytical Methods in Pharmaceuticals
- Pharmacological Receptor Mechanisms and Effects
- Pharmaceutical studies and practices
- Gastrointestinal motility and disorders
- Protein purification and stability
- Statistical Methods in Clinical Trials
- Nicotinic Acetylcholine Receptors Study
- Stress Responses and Cortisol
- Gastroesophageal reflux and treatments
- Alzheimer's disease research and treatments
- Ion channel regulation and function
- Molecular Sensors and Ion Detection
- Phosphodiesterase function and regulation
- Advanced Drug Delivery Systems
- Hormonal Regulation and Hypertension
- Bioactive Compounds and Antitumor Agents
- Crystallization and Solubility Studies
- Salivary Gland Disorders and Functions
Janssen (Belgium)
2015-2024
Medicina
2015
University of Aberdeen
2009-2014
Vanderbilt University Medical Center
2013
Vanderbilt University
2013
Duke University
2013
United States Department of Veterans Affairs
2013
Monash University
2013
University of Toronto
2013
Johnson & Johnson (Brazil)
2011
Identification of metabolic biotransformations can significantly affect the drug discovery process. Since bioavailability, activity, toxicity, distribution, and final elimination all depend on biotransformations, it would be extremely advantageous if this information could produced early in phase. Once obtained, help chemists to judge whether a potential candidate should eliminated from pipeline or modified improve chemical stability safety new compounds. The use silico methods predict site...
Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are on integration physiological, pharmacological, pharmaceutical data simulate predict behavior in vivo. Effective utilization PBBM requires consistent approach model development, verification, validation, application. Currently, only one country has draft guidance document for PBBM,...
The aim of this study was to evaluate different physiologically based modeling strategies for the prediction human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated 26 clinically tested drugs. Two mechanism-based predictions tissue-to-plasma partitioning (<i>P</i><sub>tp</sub>) from physicochemical input (method Vd1) evaluated their ability describe volume distribution at steady state (<i>V</i><sub>ss</sub>). This method compared with a strategy that combined...
The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily 7 days, followed by days’ washout. PCP-treated then PNU-120596 (10 mg/kg; s.c.) saline and were tested the attentional set-shifting task. Sub-chronic PCP produced significant deficit extra-dimensional shift (EDS) phase of task ( p < 0.001, compared with...
Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification the analogous imidazo[1,2-a]pyridine series, newly reported have improved potency, in vitro ADMET, and hERG as well good vivo PK profile. The optimization focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to scaffold substituents. Analysis this combined our previously PAMs showed how lipophilic ligand...
ABSTRACT Purpose A case example is presented in which the physiologically based modeling approach has been used to model absorption of a lipophilic BCS Class II compound predominantly metabolized by CYP3A4, and assess interplay related parameters with drug–drug interaction (DDI) potential. Methods The PBPK was built rat using Gastroplus® study characteristics compound. Subsequently relevant were predict non‐linear human PK observed during first‐in‐human after optimizing for colonic...
The aim of this study was to assess a physiologically based modeling approach for predicting drug metabolism, tissue distribution, and bioavailability in rat structurally diverse set neutral moderate-to-strong basic compounds (<i>n</i> = 50). Hepatic blood clearance (CL<sub>h</sub>) projected using microsomal data shown be well predicted, irrespective the type hepatic extraction model (80% within 2-fold). Best predictions CL<sub>h</sub> were obtained disregarding both plasma protein binding,...
The α<sub>7</sub> nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer9s disease, Parkinson9s and attention-deficit/hyperactivity disorder. Activation nAChRs improved sensory gating function in animal models early clinical trials. Here we describe novel highly selective nAChR positive allosteric modulator, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol...
In the present work we sought to gain a mechanistic understanding of physicochemical properties that influence transport unbound drug across blood-brain barrier (BBB) as well intra- and extracellular exposure in brain. Interpretable molecular descriptors significantly contribute three key neuropharmacokinetic related BBB (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), binding distribution brain (Vu,brain) for set 40 compounds were identified using partial least-squares (PLS)...
We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from HTS hit 5. In this article, we describe a different exploration 5 that led to novel subseries phenylpiperidine-substituted pyridones. The optimization strategy involved introduction spacers between pyridone core and phenyl ring fine tuning metabolism hERG followed by differentiation advanced leads were identified on basis PK profiles in vivo potency converged lead compound 36...
Advanced leads of an imidazopyridine series positive allosteric modulators the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization in vitro ADMET and vivo pharmacokinetic properties led to identification 27o. With good potency selectivity for mGlu2 receptor, 27o affected sleep-wake architecture rats after oral treatment, which we have previously shown be indicative receptor-mediated central activity.
Herein, we report the structure-activity relationship of a novel series (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On basis its robust in vitro potency vivo efficacy multiple preclinical models domains schizophrenia, coupled with good DMPK profile an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected...
Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition <i>N</i>-methyl-d-aspartate (NMDA) subtype ionotropic glutamate receptors (NMDAR) induces syndrome that recapitulates many symptoms observed patients with Selective activation metabotropic receptor 5 (mGlu<sub>5</sub>) may provide novel therapeutic approach for treatment associated schizophrenia facilitation central circuits....
Abstract Compounds modulating metabotropic glutamate type 2 ( mGlu2 ) receptor activity may have therapeutic benefits in treating psychiatric disorders like schizophrenia and anxiety. The pharmacological pharmacokinetic properties of a novel receptor‐positive allosteric modulator (PAM), 1‐butyl‐3‐chloro‐4‐(4‐phenyl‐1‐piperidinyl)‐2(1 H )‐pyridinone (JNJ‐40411813/ADX71149) are described here. JNJ‐40411813 acts as PAM at the cloned receptor: EC 50 = 147 ± 42 nmol/L [ 35 S]GTP γ S binding assay...