5259-87-0Relevant articles and documents
Lipophilic Permeability Efficiency Reconciles the Opposing Roles of Lipophilicity in Membrane Permeability and Aqueous Solubility
Naylor, Matthew R.,Ly, Andrew M.,Handford, Mason J.,Ramos, Daniel P.,Pye, Cameron R.,Furukawa, Akihiro,Klein, Victoria G.,Noland, Ryan P.,Edmondson, Quinn,Turmon, Alexandra C.,Hewitt, William M.,Schwochert, Joshua,Townsend, Chad E.,Kelly, Colin N.,Blanco, Maria-Jesus,Lokey, R. Scott
supporting information, p. 11169 - 11182 (2019/01/08)
As drug discovery moves increasingly toward previously "undruggable" targets such as protein-protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to "beyond rule of 5" molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as log D7.4dec/w - mlipocLogP + bscaffold, where log D7.4dec/w is the experimental decadiene-water distribution coefficient (pH 7.4), cLogP is the calculated octanol-water partition coefficient, and mlipo and bscaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and nonpeptidic macrocycle drugs, we show that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity.
Oxidative C-H homodimerization of phenylacetamides
Pintori, Didier G.,Greaney, Michael F.
supporting information; experimental part, p. 5713 - 5715 (2011/12/04)
A range of secondary and tertiary phenylacetamides undergo oxidative homodimerization to afford biaryls. The reaction proceeds under palladium catalysis in the presence of a copper cocatalyst and oxygen and is most effective for electron-rich substrates.
Design, synthesis, and evaluation of α-ketoheterocycles as class C β-lactamase inhibitors
Kumar, Sanjai,Pearson, Andre L.,Pratt
, p. 2035 - 2044 (2007/10/03)
A series of specific α-ketoheterocycles (benzoxazole, thiazole, imidazole, tetrazole, and thiazole-4-carboxylate) has been synthesized in order to assess their potential as β-lactamase inhibitors. The syntheses were achieved either by construction of the heterocycle (benzoxazole) from an appropriate α-hydroxyimidate, followed by oxidation of the alcohol, or by direct reaction of methyl phenaceturate with a lithiated heterocycle. The properties of these compounds in aqueous solution are described and their inhibitory activity against β-lactamases assessed. They did inhibit the class C β-lactamase of Enterobacter cloacae P99 but not the TEM β-lactamase. The most effective inhibitor of the former enzyme (Ki = 0.11 mM) was 5-(phenylacetylglycyl) tetrazole, probably because it is an anion at neutral pH. Interpretation of the results was aided by computational models of the tetrahedral adducts. Most of the compounds also inhibited α-chymotrypsin but not porcine pancreatic elastase.
