A5070099912- Neuroscience and Neuropharmacology Research
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- Microtubule and mitosis dynamics
- Pharmacological Effects and Toxicity Studies
- Nicotinic Acetylcholine Receptors Study
- Cancer Treatment and Pharmacology
- Biosimilars and Bioanalytical Methods
- HER2/EGFR in Cancer Research
- Metabolism and Genetic Disorders
- Monoclonal and Polyclonal Antibodies Research
- Amino Acid Enzymes and Metabolism
- Mitochondrial Function and Pathology
- Pharmacological Receptor Mechanisms and Effects
- Protein Degradation and Inhibitors
- Crystallization and Solubility Studies
- Neuroblastoma Research and Treatments
- Regulation of Appetite and Obesity
- X-ray Diffraction in Crystallography
- Advancements in Transdermal Drug Delivery
- Epilepsy research and treatment
Pfizer (United States)
2014-2024
Pfizer (United Kingdom)
2010
North-West University
1997-2005
Virginia Tech
1999-2002
Virginia–Maryland College of Veterinary Medicine
1999
Anglo-Boer War Museum
1970
New York State Museum
1965
Oral bioavailability (F) is a product of fraction absorbed (Fa), escaping gut-wall elimination (Fg), and hepatic (Fh). In this study, using database comprised Fa, Fg, Fh, F values for 309 drugs in humans, an analysis the interrelation physicochemical properties individual parameters was carried out order to define space optimum human oral bioavailability. Trend clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, free rotatable bonds (RB) influence...
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise increased activity. As such, inhibitors are potentially useful treatment of PD. We herein disclose discovery and optimization a novel series potent inhibitors, focusing on improving kinome selectivity using surrogate crystallography approach. This resulted...
The Biopharmaceutics Classification System (BCS) is a scientific framework that provides basis for predicting the oral absorption of drugs. These concepts have been extended in Drug Disposition (BDDCS) to explain potential mechanism drug clearance and understand effects uptake efflux transporters on absorption, distribution, metabolism, elimination. objective present work establish criteria provisional biopharmaceutics classification using pH-dependent passive permeability aqueous solubility...
Morphological changes in the lungs of macaques induced by several different LRRK2 inhibitors are reversible and do not lead to lung deficits.
3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be potent inhibitor of human DAAO, and its binding affinity confirmed Biacore assay. Cocrystallization 2 with the DAAO enzyme defined site guided design new analogues. The SAR, pharmacokinetics, brain exposure, effects on cerebellum D-serine are described. Subsequent evaluation against rat revealed divergent SAR versus may explain exposures drug necessary achieve significant changes or mouse D-serine.
Prediction of human pharmacokinetics new drugs, as well other disposition attributes, has become a routine practice in drug research and development. Prior to the 1990s, science was used mostly descriptive manner development phase. With advent vitro methods availability human-derived reagents for studies, drug-disposition scientists became engaged compound design phase discovery optimize predict properties prior nomination candidate compounds into This reaped benefits that attrition rate...
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective orthosteric agonists. Selective of positive allosteric modulator (PAM) has emerged as new approach achieve activation. This manuscript describes development series M1-selective pyridone pyridine amides their key pharmacophores. Compound 38 (PF-06767832) high...
The Aurora family of highly related serine/threonine kinases plays a key role in the regulation mitosis. Aurora1 and Aurora2 play important but distinct roles G(2) M phases cell cycle are essential for proper chromosome segregation division. Overexpression amplification have been reported different tumor types, including breast, colon, pancreatic, ovarian, gastric cancer. PF-03814735 is novel, potent, orally bioavailable, reversible inhibitor both that currently phase I clinical trials...
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed M2 M3 activation. These studies were conducted using PAMs also exhibited agonist activity, leaving open possibility direct agonism, rather than modulation, could be responsible for effects. This article describes design synthesis lactam-derived...
Abstract Objective Divergent therapeutic outcomes on different disease domains have been noted with IL-23 and IL-17A-blockade in PsA. Therefore, elucidating the role of RORγt, master regulator type 17 immune responses, is potential interest. To this end, RORγt inhibition was assessed combined skin, joint gut inflammation vivo, using a PsA model. Methods We tested efficacy antagonist B10.RIII mice challenged systemic overexpression by hydrodynamic injection enhanced episomal vector (IL-23...
Blocking chemokine receptor C-C chemoattractant cytokine (chemokine) (CCR) 6-dependent T cell migration has therapeutic promise in inflammatory diseases. PF-07054894 is a novel CCR6 antagonist that blocked only CCR6, CCR7, and C-X-C (CXCR) 2 β-arrestin assay panel of 168 G protein-coupled receptors. Inhibition CCR6-mediated human chemotaxis by (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide...
Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors the breast, ovary, stomach. It implicated in tumor growth, sensitivity standard chemotherapy, prognosis patients, disease-free survival. Although clinical use trastuzumab (Herceptin) prolonged survival breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent orally bioavailable small-molecule inhibitors. CP-724,714 a inhibitor...
Additional Supporting Information may be found in the online version of this article. Supplementary Table 1. Summary victim DDIs with rifampicin as inhibitor – OATP1B1/1B3. 2. cyclosporine OATP1B1/1B3, P-gp and BCRP. 3. probenecid OAT1/3. 4. cimetidine OCT2/MATEs. Please note: The publisher is not responsible for content or functionality any supporting information supplied by authors. Any queries (other than missing content) should directed to corresponding author
Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for treatment psychosis in multiple neurological disorders. Although development traditional activators has been stymied due to pan-receptor activation, selectivity can be achieved through utilization unique allosteric site. A major challenge capitalizing on this site date achieving balance suitable potency and brain penetration. Herein, we describe design penetrant series selective positive...
Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson's disease (PD), and pharmacological blockade LRRK2 represents a new opportunity for therapeutical treatment PD other related neurodegenerative conditions. The development an LRRK2-specific positron emission tomography (PET) ligand would enable target occupancy study vivo greatly facilitate drug discovery clinical translation as well provide molecular imaging tool studying...
Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than nonsmokers. This evidence, together with the levels brain monoamine oxidase (MAO) activity and potential neuroprotective properties MAO inhibitors, prompted studies which led to isolation characterization 2,3,6-trimethyl-1,4-naphthoquinone (TMN), an MAO-A MAO-B inhibitor is present tobacco smoke. Results experiments reported here provide that this compound protects against MPTP-mediated depletion...
Apparent intrinsic clearance (CLia) determined from microsomal stability assays is a cornerstone in drug discovery. Categorical bins are routinely applied to this end point facilitate analysis. However, such ignore the interdependent nature of apparent microsome on several ADME parameters. Considering CLia as determinant for both metabolic and potential dose more appropriate. In context with proper accounting nonspecific binding microsomes plasma, consideration compounds higher may be...