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Estimations of Octanol Solubility, Vapor Pressure, Octanol-air Partition Coefficient, and Air-water Partition Coefficient
The United States Environmental Protection Agency was established in 1970 to control, limit, and regulate pollutant entry into the environment. The primary sources of pollutants are motor vehicle emissions, chemical plants, production factories, land fills, and natural or man-made catastrophes. Persistent organic pollutants have been known to cause such aliments as cancer, respiratory disease, and birth defects. These compounds can also cause irreversible environmental effects such as ozone depletion.The amounts of pollutants in air, water, soil, and organic matter can be correlated with the octanol solubility, vapor pressure, octanol-air partition coefficient, and air-water partition coefficient. The estimation of physical properties plays an important role in understanding the fate of organic pollutants. Although it is more desirable to measure such properties, their estimations can be of great importance in conserving resources and minimizing exposure.In this dissertation new equations for the estimation of these properties are generated. This is accomplished without the use of fitted parameters or regression analysis. The only experimental input parameters are the transition temperatures. The transition properties were estimated from molecular structure. The average absolute errors for the estimated properties are less than one log unit from the experimental values
Solubility prediction in octanol: A technical note
The purpose of this work was to derive an equation for the rapid estimation of octanol solubilities of organic compounds. Solubilities ranging over 4 orders of, magnitude were predicted with an average absolute error of 0.39 logarithmic units using melting point alone. The greatest error in prediction occurred for strongly bonded compounds
Design, Synthesis, and Preclinical Evaluation of 3Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5b]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders
Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H3 receptor antagonists is described. These compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates
A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1<i>H</i>‑[1,2,3]triazolo[4,5‑<i>c</i>]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate
A single
pot dipolar cycloaddition reaction/Cope elimination sequence was developed
to access novel 1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]triazolo[4,5-<i>c</i>]pyridine P2X7 antagonists that contain a synthetically
challenging chiral center. The structure–activity relationships
of the new compounds are described. Two of these compounds, (<i>S</i>)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]triazolo[4,5-<i>c</i>]pyridin-5-yl)methanone
(compound <b>29</b>) and (<i>S</i>)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]triazolo[4,5-<i>c</i>]pyridin-5-yl)methanone
(compound <b>35</b>), were found to have robust P2X7 receptor
occupancy at low doses in rat with ED<sub>50</sub> values of 0.06
and 0.07 mg/kg, respectively. Compound <b>35</b> had notable
solubility compared to <b>29</b> and showed good tolerability
in preclinical species. Compound <b>35</b> was chosen as a clinical
candidate for advancement into phase I clinical trials to assess safety
and tolerability in healthy human subjects prior to the initiation
of proof of concept studies for the treatment of mood disorders
Identification of (<i>R</i>)‑(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro‑1<i>H</i>‑imidazo[4,5‑<i>c</i>]pyridin-5(4<i>H</i>)‑yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor
The synthesis and
SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-<i>c</i>]pyridine P2X7 antagonists are described. Addressing P2X7
affinity and liver microsomal stability issues encountered with this
template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-<i>c</i>]pyridines ultimately leading to the identification of <b>1</b> (JNJ 54166060). <b>1</b> is a potent P2X7 antagonist
with an ED<sub>50</sub> = 2.3 mg/kg in rats, high oral bioavailability
and low-moderate clearance in preclinical species, acceptable safety
margins in rats, and a predicted human dose of 120 mg of QD. Additionally, <b>1</b> possesses a unique CYP profile and was found to be a regioselective
inhibitor of midazolam CYP3A metabolism