Author
Scot Richard Mente
Other affiliations: Pennsylvania State University
Bio: Scot Richard Mente is an academic researcher from Pfizer. The author has contributed to research in topics: Casein kinase 1 & Schizophrenia. The author has an hindex of 17, co-authored 41 publications receiving 949 citations. Previous affiliations of Scot Richard Mente include Pennsylvania State University.
Topics: Casein kinase 1, Schizophrenia, Agonist, Circadian rhythm, Dementia
Papers
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TL;DR: In this paper, computer simulations are performed in order to investigate the role of hydroxylic solvents in catalyzing the excited-state tautomerization of 7-azaindole (7-AI) and 1-azacarbazole (1-AC).
Abstract: Computer simulations are performed in order to investigate the role hydroxylic solvents play in catalyzing the excited-state tautomerization of 7-azaindole (7-AI) and 1-azacarbazole (1-AC). Classical Monte Carlo and molecular dynamics methods are used to test the idea that reaction rates in these systems are controlled primarily by the fraction of solutes that are “correctly” solvated. Assuming that correct solvation involves formation of a cyclic 1:1 solute−solvent complex, reactive fractions are computed for a series of eight hydroxylic solvents: methanol, ethanol, 1-propanol, 2,2,2-trifluoroethanol, 2-propanol, tert-butyl alcohol, ethylene glycol, and water. In all cases the reactive fractions so calculated are small (<2%) and are of the correct magnitude to account for the relatively slow reaction observed in neat solvents. The underlying cause for these small reactive populations can be rationalized on the basis of the weak hydrogen bonds afforded by a cyclic arrangement. In nearly all cases these f...
123 citations
TL;DR: Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
Abstract: 3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
108 citations
TL;DR: In this paper, Monte Carlo simulations of the pyridinium N-phenolate dye "Betaine-30" in 12 solvents (20 solvent representations) were performed in order to explore the molecular basis of the ET(30) scale of solvent polarity.
Abstract: Monte Carlo simulations of the pyridinium N-phenolate dye “betaine-30” in 12 solvents (20 solvent representations) were performed in order to explore the molecular basis of the ET(30) scale of solvent polarity. Ab initio (HF/6-31G*) and semiempirical (AM1 and INDO/S) electronic structure calculations were used to determine the geometry and charge distribution of betaine-30 in its S0 and S1 states. The solvent effect on the betaine absorption spectrum was assumed to derive from electrostatic interactions between the effective charge distributions of solvent molecules and the charge shift brought about by the S0 → S1 transition. Two models for this charge shift, one obtained from INDO/S calculations and the other an idealized two-site model, were used for the spectral calculations. Good agreement between simulated and observed ΔET shifts (ET(30) values measured relative to the nonpolar standard tetramethylsilane) was found for both charge-shift models. In water and other hydroxylic solvents, the O atom of t...
91 citations
TL;DR: Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving the initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.
Abstract: The discovery of two histamine H3 antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, “best-in-class” molecules.
66 citations
TL;DR: A high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages inαSN aggregation is developed and several phenyl-benzoxazol compounds that promoted α SN aggregation (proaggregators) are identified, which may be useful tools to modulate β-Synuclein aggregation in cellula.
65 citations
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TL;DR: The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or her own research.
Abstract: I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or
7,563 citations
Book•
17 May 2013
TL;DR: This research presents a novel and scalable approach called “Smartfitting” that automates the very labor-intensive and therefore time-heavy and therefore expensive and expensive process of designing and implementing statistical models for regression models.
Abstract: General Strategies.- Regression Models.- Classification Models.- Other Considerations.- Appendix.- References.- Indices.
3,672 citations
TL;DR: The reaction types used in the pursuit of novel drug candidates are analyzed to evaluate their frequency of occurrence, alongside other factors such as drug likeness, chirality, and the number of steps to each derivative.
Abstract: The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
1,712 citations
594 citations
TL;DR: This work systematically gives a comprehensive review in current developments of imidazole‐based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti‐inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology.
Abstract: Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.
558 citations