A5071208746- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Antibiotics Pharmacokinetics and Efficacy
- Cannabis and Cannabinoid Research
- Pharmacological Effects and Toxicity Studies
- Neurotransmitter Receptor Influence on Behavior
- Receptor Mechanisms and Signaling
- Crystallization and Solubility Studies
- Neuropeptides and Animal Physiology
- X-ray Diffraction in Crystallography
- Analytical Chemistry and Chromatography
- Neuroscience and Neuropharmacology Research
- Diabetes Treatment and Management
- Pharmacology and Obesity Treatment
- Electrochemical Analysis and Applications
- RNA and protein synthesis mechanisms
- Cancer therapeutics and mechanisms
- RNA modifications and cancer
- Diet and metabolism studies
- Veterinary Pharmacology and Anesthesia
- Regulation of Appetite and Obesity
- Pancreatic function and diabetes
- Lipid Membrane Structure and Behavior
- GABA and Rice Research
Pfizer (United States)
2010-2020
University of California, San Francisco
2015-2018
Renewable Energy Systems (United States)
2015
World Wide Web Consortium
2014
University of Michigan
2006
University of Kansas
1989-1993
Unbound fractions in mouse brain and plasma were determined for 31 structurally diverse central nervous system (CNS) drugs two active metabolites. Three comparisons made between vitro binding vivo exposure data, namely: 1) brain-to-plasma versus unbound plasma-to-unbound fraction ratio (fu<sub>plasma</sub>/fu<sub>brain</sub>), 2) cerebrospinal fluid-to-brain (fu<sub>brain</sub>), 3) fluid-to-plasma (fu<sub>plasma</sub>). data within 3-fold of ratios the majority examined (i.e., 22 33),...
Species independence of brain tissue binding was assessed with a large number structurally diverse compounds using equilibrium dialysis homogenates seven species and strains (Wistar Han rat, Sprague-Dawley CD-1 mouse, Hartley guinea pig, beagle dog, cynomolgus monkey, human). The results showed that the fractions unbound were strongly correlated correlation coefficients ranging from 0.93 to 0.99. cross-species/strain correlations not significantly different interassay same species. linear...
Significant progress has been made in structure-based drug design by pharmaceutical companies at different stages of discovery such as identifying new hits, enhancing molecule binding affinity hit-to-lead, and reducing toxicities lead optimization. Drug metabolism is a major consideration for modifying clearance also primary source metabolite-induced toxicity. With cytochrome P450 structures identified characterized recently, prediction becomes increasingly attractive. In silico methods...
Characterization of patterns wheezing and allergic sensitization in early life may allow for identification specific environmental exposures impacting asthma development.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSampling living systems using microdialysis probesCraig E. Lunte, Dennis O. Scott, and Peter T. KissingerCite this: Anal. Chem. 1991, 63, 15, 773A–780APublication Date (Print):August 1, 1991Publication History Published online22 September 2008Published inissue 1 August 1991https://pubs.acs.org/doi/10.1021/ac00015a001https://doi.org/10.1021/ac00015a001research-articleACS PublicationsRequest reuse permissionsArticle...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIntravenous microdialysis sampling in awake, freely-moving ratsMartin. Telting-Diaz, Dennis O. Scott, and Craig E. LunteCite this: Anal. Chem. 1992, 64, 7, 806–810Publication Date (Print):April 1, 1992Publication History Published online1 May 2002Published inissue 1 April 1992https://pubs.acs.org/doi/10.1021/ac00031a019https://doi.org/10.1021/ac00031a019research-articleACS PublicationsRequest reuse permissionsArticle...
Because of the importance intracellular unbound drug concentrations in prediction vivo that are determinants efficacy and toxicity, a number assays have been developed to assess vitro drugs. Here we present rapid method determine cultured cells, apply along with mechanistic model predict metformin subcellular compartments stably transfected human embryonic kidney 293 (HEK293) cells. Intracellular space (ICS) was calculated by subtracting [<sup>3</sup>H]-inulin distribution volume...
Estimation of unbound fraction substrate in microsomal incubation media is important accurately predicting hepatic intrinsic clearance and drug-drug interactions. In this study, the 1223 drug-like molecules human liver has been determined using equilibrium dialysis. These compounds, which include 27 marketed drug molecules, cover a much broader range physiochemical properties such as hydrophobicity, molecular weight, ionization state, degree binding than those examined previous work....
We report the structure−activity relationships, design, and synthesis of novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) functional assays 0.12 nM). In vivo, compound reversed agonist-mediated responses, reduced food intake, increased energy expenditure fat oxidation rodents.
Abstract Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate described that inhibits ribosomal synthesis PCSK9, lipid regulator considered undruggable by small molecules. Key to concept was identification pharmacologically active zwitterions designed be retained in liver. Oral delivery poorly permeable achieved prodrugs susceptible cleavage carboxylesterase 1. The select tetrazole crucial....
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
Abstract CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 agonist. stimulates trabecular and cortical bone formation restores mass strength in aged ovariectomized rats with established osteopenia. Introduction: The purpose of this study was to determine whether (PGE2) agonist, CP432, could produce anabolic effects aged, (OVX) Materials Methods: at 0.3, 1, or 3 mg/kg/day given for 6 weeks by subcutaneous injection 12-month-old that had been OVX 8.5 months. on...
4-Aminopiperidines are a variety of therapeutic agents that extensively metabolized by cytochrome P450s with CYP3A4 as major isoform catalyzing their N-dealkylation reaction. However, its catalytic mechanism has not been fully elucidated in molecular interaction level. Here, we applied theoretical approaches including the mechanics-based docking to study binding patterns and quantum reactivity calculations. They were supported experimental human liver microsomal clearance P450 phenotyping...
We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members these series are potent, selective antagonists in vitro/in vivo efficacy models CB(1) antagonism exhibit robust oral activity rodent food intake. These efforts led to identification 19d, which has been advanced human clinical trials for weight management.
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...
Fluorine- and chlorine-containing moieties have been strategically integrated into chemical structures to optimize the pharmacokinetic metabolic properties of therapeutic agents, based partly on concept that addition these substituents may lower microsomal clearance. A large-scale systematic mechanistic study drug alteration by aromatic halogenation has hitherto not possible due lack either large clearance databases or adequate data mining tools. To address this, we systematically searched...
Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development lead drugs against this target. However, peripherally restricted CB1 antagonists may hold potential for providing desired efficacy with reduced CNS effect profiles. In report we detail discovery structure-activity-relationship analysis a novel bicyclic scaffold (3) that...