- Optimization of Orally Bioavailable PI3KδInhibitors and Identification of Vps34 as a Key Selectivity Target
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Optimization of a lead series of PI3Kδinhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδover Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
- Henley, Zo? A.,Amour, Augustin,Barton, Nick,Bantscheff, Marcus,Bergamini, Giovanna,Bertrand, Sophie M.,Convery, Máire,Down, Kenneth,Dümpelfeld, Birgit,Edwards, Chris D.,Grandi, Paola,Gore, Paul M.,Keeling, Steve,Livia, Stefano,Mallett, David,Maxwell, Aoife,Price, Mark,Rau, Christina,Reinhard, Friedrich B. M.,Rowedder, James,Rowland, Paul,Taylor, Jonathan A.,Thomas, Daniel A.,Hessel, Edith M.,Hamblin, J. Nicole
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supporting information
p. 638 - 655
(2020/02/04)
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- Synthesis of (E)-1-benzyloxy-3-fluoro-1,3-butadiene: A novel fluorinated diene for Diels-Alder reactions
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A new approach has been developed for the synthesis of the fluorinated Kitahara-Danishefskys diene analogue, (E)-1-benzyloxy-3-fluoro-1,3-butadiene, via a Pd-catalyzed process. This novel fluorine-containing diene reacts with various dienophiles to provide useful 1-fluorocyclohexene derivatives in good yields. Georg Thieme Verlag Stuttgart - New York.
- Hayashi, Tsuyoshi,Usuki, Yoshinosuke,Wakamatsu, Yosuke,Iio, Hideo
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supporting information; body text
p. 2843 - 2846
(2011/02/16)
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- BENZOISOINDOLE DERIVATIVES AND THEIR USE AS EP4 RECEPTOR LIGANDS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R1 to R8, X and Y are as defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of s
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Page/Page column 24
(2008/06/13)
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- Phthalazine derivatives and remedies for erectile dysfunction
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The present invention provides a phthalazine compound as a therapeutic agent for erectile dysfunction represented by the following formula, a pharmacologically acceptable salt thereof or a hydrate thereof: wherein R1and R2are the same as or different from each other and represent a halogen atom, a C1 to C4 alkyl group which may be substituted with a halogen atom, a C1 to C4 alkoxy group which may be substituted with a halogen atom or a cyano group; X represents a cyano group, a nitro group, a halogen atom, a hydroxyimino group which may be substituted or a heteroaryl group which may be substituted; Y represents a heteroaryl group, an aryl group which may be substituted, an alkynyl group which may substituted, an alkenyl group, an alkyl group, an optionally substituted saturated or unsaturated 4- to 8-membered amine ring, and the cyclic amine compound is a monocyclic compound, bicyclic compound or a spiro compound; l is an integer of 1 to 3; provided that the case where l is 1 or 2, X is a cyano group, a nitro group or a chlorine atom, R1is a chlorine atom, R2is a methoxy group and Y is a 5- or 6-membered amine ring substituted with a hydroxyl group is excluded.
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- Synthesis of 4-substituted phthalic anhydrides
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Disclosed is a method of making a 4-substituted phthalic anhydride. A halomaleic (including halofumaric anhydride (or the acid or ester thereof) is made by the reaction of-maleic anhydride with chlorine or bromine. The halomaleic anhydride is reacted with a conjugated diene to form a first cycloadduct having the formula STR1 The first cycloadduct is heated to eliminate HX and produce a second cycloadduct having the formula STR2 The second cyclo adduct is dehydrogenated to produce a 4substituted phthalic anhydride which has the formula STR3 where R1, R2, and R4 are preferably H and R3 is preferably Cl or F.
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- The Diels-Alder approach to musk odor type arenes
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The readily accessible 2-halogeno-1-trimethylsilyloxy-1,3-butadienes react smoothly with dimethyl acetylenedicarboxylate to afford 4-halophthalic esters. One of these cycloadducts was subsequently converted into heterocyclic analogues of phantolide like musk fragrances.
- Shi,Cottens,Shiba,Schlosser
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p. 10569 - 10574
(2007/10/02)
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