Christopher R. Jones

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDetermination of Rate Constants for Complex Kinetics ModelsD. M. Himmelblau, C. R. Jones, and K. B. BischoffCite this: Ind. Eng. Chem. Fundamen. 1967, 6, 4, 539–543Publication Date (Print):November 1, 1967Publication History Published online1 May 2002Published inissue 1 November 1967https://pubs.acs.org/doi/10.1021/i160024a008https://doi.org/10.1021/i160024a008research-articleACS PublicationsRequest reuse permissionsArticle Views952Altmetric-Citations122LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options Get e-Alerts

Whether nonconventional hydrogen bonds, such as the C-H···O interaction, are a consequence or a determinant of conformation is a long-running and unresolved issue. Here we outline a solid-state and quantum mechanical study designed to investigate whether a C-H···O interaction can override the significant trans-planar conformational preferences of α-fluoroamide substituents. A profound change in dihedral angle from trans-planar((OCCF)) to cis-planar((OCCF)) observed on introducing an acceptor group for a C-H···O hydrogen bond is consistent with this interaction functioning as a determinant of conformation in certain systems. This testifies to the potential influence of the C-H···O hydrogen bond and is consistent with the assignment of this interaction as a contributor to overall conformation in both model and natural systems.

The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.

Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.