cas 4728-12-5, 2,2-Dimethyl-5-(hydroxymethyl)-1,3-dixoane

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Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase
Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). On the basis of this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N9 atom of guanine to one of the phosphonate groups. The crystal structure of this ANbP in complex with human HGPRT was determined at 2.0 ? resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC50 values in the low micromolar range in Pf lines and low toxicity in human A549 cells, demonstrating that these ANbPs are excellent antimalarial drug leads.
?pa?ek, Petr,Keough, Dianne T.,Chavchich, Marina,Dra?ínsky, Martin,Janeba, Zlatko,Naesens, Lieve,Edstein, Michael D.,Guddat, Luke W.,Hocková, Dana
p. 7539 - 7554
(2017)
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GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer
Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
Liang, Jun,Zbieg, Jason R.,Blake, Robert A.,Chang, Jae H.,Daly, Stephen,Dipasquale, Antonio G.,Friedman, Lori S.,Gelzleichter, Thomas,Gill, Matthew,Giltnane, Jennifer M.,Goodacre, Simon,Guan, Jane,Hartman, Steven J.,Ingalla, Ellen Rei,Kategaya, Lorn,Kiefer, James R.,Kleinheinz, Tracy,Labadie, Sharada S.,Lai, Tommy,Li, Jun,Liao, Jiangpeng,Liu, Zhiguo,Mody, Vidhi,McLean, Neville,Metcalfe, Ciara,Nannini, Michelle A.,Oeh, Jason,O'Rourke, Martin G.,Ortwine, Daniel F.,Ran, Yingqing,Ray, Nicholas C.,Roussel, Fabien,Sambrone, Amy,Sampath, Deepak,Schutt, Leah K.,Vinogradova, Maia,Wai, John,Wang, Tao,Wertz, Ingrid E.,White, Jonathan R.,Yeap, Siew Kuen,Young, Amy,Zhang, Birong,Zheng, Xiaoping,Zhou, Wei,Zhong, Yu,Wang, Xiaojing
supporting information
p. 11841 - 11856
(2021/07/31)

Synthesis of Panal Terpenoid Core
Panal is a natural bicyclic cadalane-type sesquiterpenoid with an unusual combination of stereocenters. It was isolated in 1988 as an alleged biosynthetic precursor of luciferin (a light-emitting molecule) in a bioluminescent fungus Panellus stipticus. Herein we present the first approach to the synthesis of the terpenoid skeleton of panal, which includes construction of five stereocenters, one of which is easily epimerizable. The key steps in the synthetic approach presented are high-pressure Diels-Alder reaction disobeying the ‘endo rule’, Barbier reductive allylation, and cyclization of trans-decalin ring via ring-closing metathesis.
Baranov, Mikhail S.,Kaskova, Zinaida M.,Gritсenko, Roman,Postikova, Svetlana G.,Ivashkin, Pavel E.,Kislukhin, Alexander A.,Moskvin, Dmitrii I.,Mineev, Konstantin S.,Arseniev, Alexander S.,Labas, Yulii A.,Yampolsky, Ilia V.
p. 583 - 588
(2017/03/11)

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs
Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower Ki values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest Ki values obtained for the two parasite enzymes were 0.1?μM (Pf) and 0.2?μM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5?μM. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300?μM resulting in an excellent selectivity index.
?pa?ek, Petr,Keough, Dianne T.,Chavchich, Marina,Dra?ínsky, Martin,Janeba, Zlatko,Naesens, Lieve,Edstein, Michael D.,Guddat, Luke W.,Hocková, Dana
p. 4008 - 4030
(2017/07/05)

BICYCLIC HETEROARYL UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS
Compounds of Formula I or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.
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Paragraph 00651

(2014/06/11)

ANTIBACTERIAL AGENTS
Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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(2013/12/03)

ARYL GLYCOSIDE COMPOUND, PREPARATION METHOD AND USE THEREOF
Disclosed are an aryl glycoside compound as represented by formula I or formular I′, a pharmaceutically acceptable salt thereof, optical isomer thereof or a prodrug thereof. The present invention relates to a method of preparing said aryl glycoside compound and the use thereof The aryl glycoside compound of the present invention has an excellent ability on inhibit SGLT activity, especially SGLT2 activity, and is diabetes-fighting medicine with great potential.
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Paragraph 0137; 0138

(2014/01/07)

ARYL GLYCOSIDE COMPOUND, PREPARATION METHOD AND USE THEREOF
Disclosed are an aryl glycoside compound as represented by formula I or formular I', a pharmaceutically acceptable salt thereof, optical isomer thereof or a prodrug thereof. The present invention relates to a method of preparing said aryl glycoside compound and the use thereof. The aryl glycoside compound of the present invention has an excellent ability on inhibit SGLT activity, especially SGLT2 activity, and is diabetes-fighting medicine with great potential.
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Paragraph 0093; 0094

(2014/01/09)

Development of a practical and scalable synthesis of (R)- and (S)-3-amino-2-[(benzyloxy)methyl]propan-1-ol monohydrochloride: A useful C-4 Chiral Building Block
The development of a practical and scalable synthesis of a C-4 chiral amine building block (R)-1·HCl and (S)-1·HCl is described. This important chiral intermediate (R)-1·HCl is efficiently synthesized from the commercially available, inexpensive, and simple 2-(hydroxymethyl)-1,3- propanediol (31) using lipase-catalyzed enantioselective hydrolysis as a key reaction. Development resulted in a telescoped process that was operated successfully and reproducibly in a pilot-plant-scale synthesis, and 22 kg of chiral amine (R)-1·HCl was prepared in the first scale-up synthesis. This synthetic method is also useful for preparation of the important chiral building block (S)-1·HCl, which is the enantiomer of (R)-1·HCl.
Yoshida, Shinya,Obitsu, Kazuyoshi,Hayashi, Yasumasa,Shibazaki, Mitsuyoshi,Kimura, Takenori,Takahashi, Takumi,Asano, Toru,Kubota, Hirokazu,Mukuta, Takashi
p. 1527 - 1537
(2013/02/23)

Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands
We designed and synthesized nonsecosteroidal vitamin D receptor (VDR) ligands that formed H-bonds with six amino acid residues (Tyr143, Ser233, Arg270, Ser274, His301 and His393) of the VDR ligand-binding domain. The ligand YR335 exhibited potent transcriptional activity, which was comparable to those of 1α,25-dihydroxyvitamin D3 and YR301. The crystal structure of the complex formed between YR335 and the VDR ligand-binding domain was solved, which revealed that YR335 formed H-bonds with the six amino acid residues mentioned above.
Demizu, Yosuke,Takahashi, Takeo,Kaneko, Fumiya,Sato, Yukiko,Okuda, Haruhiro,Ochiai, Eiji,Horie, Kyohei,Takagi, Ken-Ichiro,Kakuda, Shinji,Takimoto-Kamimura, Midori,Kurihara, Masaaki
scheme or table
p. 6104 - 6107
(2011/11/06)

3,5-Disubstituted pyranone analogues of highly antifungally active furanones: Conversion of biological effect from antifungal to cytostatic
A series of 3-aryl-5-acyloxymethyl-5,6-dihydro-2H-pyran-2-ones, related to highly antifungally active butenolides, was synthesized via cyclization of substituted δ-hydroxy acids as the key step, and evaluated for their in vitro antifungal activity and cytostatic activity. While the extension of the furanone ring to pyranone led to a complete loss of the antifungal effect, some of the compounds displayed promising effect against several cell lines, including the resistant colorectal carcinoma cells.
Schiller, Radan,Tichotová, Lucie,Pavlík, Jan,Buchta, Vladimír,Melichar, Bohuslav,Votruba, Ivan,Kune?, Ji?í,?pulák, Marcel,Pour, Milan
p. 7358 - 7360
(2011/01/12)

2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
The invention relates to 2-phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y12 receptor antagonists in the treatment and/or prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. Formula (I).
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Page/Page column 29

(2010/01/29)

Fluorinated benzofuran derivatives for PET imaging of β-amyloid plaques in alzheimer's disease brains
A series of fluorinated benzofuran derivatives as potential tracers for positron emission tomography (PET) targeting β-amyloid plaques in the brains of patients with Alzheimer's disease (AD) were synthesized and evaluated. The derivatives were produced using an intramolecular Wittig reaction. In experiments in vitro, all displayed high affinity for Aβ(1-42) aggregates with Ki values in the nanomolar range. Radiofluorinated 17, [ 18F]17, in particular labeled β-amyloid plaques in sections of Tg2576 mouse brain and displayed high uptake (5.66% ID/g) at 10 min postinjection, sufficient for PET imaging. In addition, in vivo β-amyloid plaque labeling can be clearly demonstrated with [18F]17 in Tg2576 mice. In conclusion, [18F]17 may be useful for detecting β-amyloid plaques in patients with AD.
Cheng, Yan,Ono, Masahiro,Kimura, Hiroyuki,Kagawa, Shinya,Nishii, Ryuichi,Kawashima, Hidekazu,Saji, Hideo
scheme or table
p. 321 - 325
(2010/12/18)

BENZOXAZOLE DERIVATIVES
It is intended to provide a benzoxazole derivative or a pharmaceutically acceptable salt or solvate thereof which is useful in the early diagnosis of a conformation disease; a composition or a kit containing the same for diagnosing a conformation disease; a medical composition for ttreating and/or preventing a conformation disease; and so on.
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Page/Page column 51-52

(2009/10/01)

2-[2-Substituted-3-(3,4-dichlorobenzylamino)propylamino]-1H-quinolin-4-ones as Staphylococcus aureus methionyl-tRNA synthetase inhibitors
New analogues of 2-[2-substituted-3-(3,4-dichlorobenzylamino)propylamino]quinolin-4-ones, 26a, 26b, 31a-e, 34, 35, 38 and 40, have been synthesized and evaluated against Staphylococcus aureus methionyl-tRNA synthetase. All of the synthesized compounds were less active than the reference compound 2. The compounds were also screened against various strains of S. aureus and Enterococci for their antibacterial activities. Among the compounds, 26b, 31c and 31e displayed significant inhibitory properties against various strains of Enterococci compared to compound 2.
Farhanullah,Kang, Taehee,Yoon, Eun-Jung,Choi, Eun-Chil,Kim, Sunghoon,Lee, Jeewoo
experimental part
p. 239 - 250
(2009/04/07)

CATIONIC LIPIDS AND USES THEREOF
Cationic lipids, cationic lipid based drug delivery systems, ways to make them and methods of treating diseases using them are disclosed.
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Page/Page column 84

(2009/12/02)

2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR
The invention relates to 2-phenyl-6-aminbcarbonyl-pyrimidinc derivatives and their use as P2Y12 receptor antagonists in the treatment and/or prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. Formula (1).
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Page/Page column 17-18

(2009/12/05)

BENZIMIDAZOLE COMPOUND HAVING GASTRIC ACID SECRETION INHIBITORY ACTIVITY
The present invention provides a compound that has superior gastric acid secretion inhibitory action, ample long-lasting gastric acid secretion inhibitory action, and is able to maintain intragastric pH at a high level for an extended period of time, making it useful as a therapeutic or prophylactic agent for diseases or symptoms caused by gastric acid, as well as an active form of this compound (form to which the compound is converted in the body following administration thereof) in the form of a compound represented by general formula (1 a) (wherein R2 represents a group represented by formula (I) or the like, and R1, R3, W1 and X- are as defined in the description).
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Page/Page column 18-19

(2009/06/27)

SALT OF SULFINYLBENZIMIDAZOLE COMPOUND, AND CRYSTAL AND AMORPHOUS FORM THEREOF
Salts of 2-[({4-[(2.2-dimethyl-1,3-dioxan-5-yl)methoxy]-3,5-dimethylpyridin-2-yl}methyl)sulfinyl]-1H-benzimidazole and their crystalline and amorphous forms.
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Page/Page column 15

(2009/07/18)

Pyrazole glucokinase activators
Disclosed herein are pyrazole glucokinase activators of the formula (I) useful for the treatment of metabolic diseases and disorders, preferably diabetes mellitus.
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(2008/06/13)

BORON-CONTAINING SMALL MOLECULES
This invention provides, among other things, novel compounds useful for treating bacterial infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.
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Page/Page column 210

(2009/01/23)

DEVELOPMENT OF MOLECULAR IMAGING PROBES FOR CARBONIC ANHYDRASE-IX USING CLICK CHEMISTRY
The present application discloses methods for identifying inhibitors with high binding-affinity for the carbonic anhydrase-IX (CA-IX) enzyme using click chemistry and uses the candidates thereof as positron emission tomography (PET) imaging agents.
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Page/Page column 84

(2008/12/04)

CHEMICAL COMPOUNDS
The present invention relates to compounds that are a non-nucleoside reverse transcriptase inhibitors, and to processes for the preparation and use of the same. Specifically, the present invention includes methods of using such compounds in the treatment of human immunodeficiency virus infection.
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Page/Page column 67-68

(2009/01/24)

SUBSTITUTED PYRAZOLE AND TRIAZOLE COMPOUNDS AS KSP INHIBITORS
Disclosed are new substituted pyrazole and triazole compounds of Formula (I) and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the derivatives together with pharmaceutically acceptable carriers, and uses thereof
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Page/Page column 54

(2008/12/05)

CYCLIZED DERIVATIVES AS EG-5 INHIBITORS
The present invention relates to new substituted imidazole compounds have the following Formula (I) and to the pharmaceutically acceptable salts, esters, or prodrugs thereof, to compositions of the compounds together with pharmaceutically acceptable carriers, and to uses of the compounds: (I).
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Page/Page column 75

(2008/12/07)

CHEMICAL COMPOUNDS
The present invention relates to compounds that are a non-nucleoside reverse transcriptase inhibitors, and to processes for the preparation and use of the same. Specifically, the present invention includes methods of using such compounds in the treatment of human immunodeficiency virus infection.
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Page/Page column 67

(2009/01/23)

PROCESS FOR THE PRODUCTION OF 2- [ [4- T (2, 2-DIMETHYL-1, 3-DIOXAN-5-YL) METHOXY] PYRIDIN-2-YL] METHYLTHIO] -1H-BENZIMIDAZOLE
It is an object of the present invention to provide a process for the production on an industrial scale of a compound (1) or a salt thereof. There is provided a process for the production of compound (1) represented by the formula or a salt thereof: (wherein R1 and R3 independently represents a hydrogen atom or a methyl group), the process comprising the steps of: (a) reacting together a compound (3T) represented by the formula: (wherein X1 represents a leaving group, and R1 and R3 are defined as above) and (2,2-dimethyl-1,3-dioxan-5-yl)methanol represented by the formula or a salt thereof: so as to produce a compound (2T) represented by the formula (wherein R1 and R3 are defined as above); and (b) reacting the compound represented by above formula (2T) with an oxidizing agent.
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Page/Page column 38

(2008/12/05)

Facile synthesis of (±)-paeonilide
(Chemical Equation Presented) (±)-Paeonilide, a novel monoterpenoid metabolite from the roots of Paeonia delavayi showing anti-platelet activating factor activity, is convergently synthesized in five steps with 59% overall yield. The application of benzoyl peroxide-promoted radical addition of unsaturated ester to aldehyde and subsequent topologically favored cyclization greatly simplified the synthesis.
Du, Yuguo,Liu, Jun,Linhardt, Robert J.
p. 3952 - 3954
(2008/02/01)

Bifunctional acyclic nucleoside phosphonates: 2. Symmetrical 2-{[bis(phosphono)methoxy]methyl}ethyl derivatives of purines and pyrimidines
Novel bisphosphonate alkylating agent, tetraisopropyl (2-[(mesyloxy)methyl] propane-1,3-diyl]bis(oxymethylene)bisphosphonate 19, was synthesized from diethyl 2,2-bis-(hydroxymethyl)malonate. Decarbethoxylation of the diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate was followed by chloromethylation of 2-[(benzyloxy)methyl]propane-1,3-diol and Arbuzov reaction with triisopropyl phosphite. Bisphosphonate building block 19 was used in the alkylation of various nucleobases (2-amino-6-chloropurine, adenine, 2-amino-6-(cyclopropyl) aminopurine, cytosine, uracil and 4-methoxy-5-methylpyrimidin-2(1H)-one). N 9-Substituted purines and N1-substituted pyrimidines were converted to appropriate free bisphosphonic acids. No antiviral or cytostatic activity was detected.
Vrbkova, Silvie,Dracinsky, Martin,Holy, Antonin
p. 965 - 983
(2008/09/20)

Benzimidazole compound
An object of the present invention is to provide a novel chemical compound useful as a therapeutic or prophylactic agent for acid-related diseases, having an excellent inhibitory effect against gastric acid secretion, an excellent effect of maintaining the inhibitory effect against gastric acid secretion, thereby maintaining intragastric pH high for a long time, and having more safety and appropriate physicochemical stability. Provided is a compound represented by where R1 and R3 may be the same or different and each represent a hydrogen atom or a C1-C6 alkyl group; R2 represents (5,5-dimethyl-1,3-dioxan-2-yl)methoxy group, 5,7-dioxaspiro[2.5]oct-6-ylmethoxy group, 1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy group, or (2,2-dimethyl-1,3-dioxan-5-yl)methoxy group; R4, R5, R6 and R7 represent a hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group or C1-C6 haloalkoxy group; and W1 represents a single bond, methylene or ethylene group, a salt thereof or a solvate of these.
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Page/Page column 38

(2008/06/13)

Synthesis of cluster mannosides carrying a photolabile diazirine group
We are investigating the mechanisms underlying the carbohydrate-specific adhesion of bacteria such as Escherichia coli to the glycocalyx of their potential host cells. E. coli possess protein appendages, which are called type 1 fimbriae. Part of type 1 fimbriae is a protein named FimH, which is a mannose-specific lectin. We wish to use photoaffinity labeling to elucidate mannose binding sites on FimH. Thus we report the synthesis of di- and trivalent cluster mannosides, which carry a photolabile diazirine group. The diazirine group was introduced by a convergent approach using thiourea bridging (products 6, 13, 17, and 27) or in a divergent synthesis leading to the divalent cluster mannoside 31. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
Walter, Mark,Wiegand, Michaela,Lindhorst, Thisbe K.
p. 719 - 728
(2007/10/03)

THIENO [2,3-D] PYRIMIDINE COMPOUNDS AS INHIBITORS OF ADP-MEDIATED PLATELETS AGGREGATION
Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I): wherein A1, A2, A3, A4, A5, A6, A7, A8, X4, X6, R2, R4, R5, and R6 are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
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Page/Page column 91

(2008/06/13)

F-18 stilbenes as PET imaging agents for detecting β-amyloid plaques in the brain
Imaging agents targeting β-amyloid (Aβ) may be useful for diagnosis and treatment of patients with Alzheimer's disease (AD). Compounds 3e and 4e are fluorinated stilbene derivatives displaying high binding affinities for Aβ plaques in AD brain homogenates (Ki = 15 ± 6 and 5.0 ± 1.2 nM, respectively). In vivo biodistributions of [ 18F]Se and [18F]4e in normal mice exhibited excellent brain penetrations (5.55 and 9.75% dose/g at 2 min), and rapid brain washouts were observed, especially for [18F]4e (0.72% dose/g at 60 min). They also showed in vivo plaque labeling in APP/PS1 or Tg2576 transgenic mice, animal models for AD. Autoradiography of postmortem AD brain sections and AD homogenate binding studies confirmed the selective and specific binding properties to Aβ plaques. In conclusion, the preliminary results strongly suggest that these fluorinated stilbene derivatives, [18F]3e and [18F]4e, are suitable candidates as Aβ plaque imaging agents for studying patients with AD.
Zhang, Wei,Oya, Shunichi,Kung, Mei-Ping,Hou, Catherine,Maier, Donna L.,Kung, Hank F.
p. 5980 - 5988
(2007/10/03)

Enzyme assisted syntheses of chiral building blocks for isosters of diglycerides, phospholipids and PAF
Lipase catalyzed desymmetrizations of suitably substituted, achiral 1,3-diols lead to the corresponding chiral building blocks of high enantiomeric purities, starting materials for the synthesis of isosteric carba-analogues of 1,2-sn-diglycerides and phospholipids with interesting biological activities. Lipase catalyzed resolutions of the corresponding ether derivatives lead to the corresponding building blocks for carba-analogues of PAF.
Lange, Karsten,Schneider, Manfred P.
p. 2811 - 2815
(2007/10/03)

Acyclic analogues of adenosine bisphosphates as P2Y receptor antagonists: Phosphate substitution leads to multiple pathways of inhibition of platelet aggregation
Activation by ADP of both P2Y1 and P2Y12 receptors in platelets contributes to platelet aggregation, and antagonists at these receptor subtypes have antithrombotic properties. In an earlier publication, we have characterized the SAR as P2Y1 receptor antagonists of acyclic analogues of adenine nucleotides, containing two phosphate groups on a symmetrically branched aliphatic chain, attached at the 9-position of adenine. In this study, we have focused on antiaggregatory effects of P2Y antagonists related to a 2-chloro-N6-methyladenine-9-(2-methylpropyl) scaffold, containing uncharged substitutions of the phosphate groups. For the known nucleotide (cyclic and acyclic) bisphosphate antagonists of P2Y1 receptors, there was a significant correlation between inhibition of aggregation induced by 3.3 μM ADP in rat platelets and inhibition of P2Y1 receptor-induced phospholipase C (PLC) activity previously determined in turkey erythrocytes. Substitution of the phosphate groups with nonhydrolyzable phosphonate groups preserved platelet antiaggregatory activity. Substitution of one of the phosphate groups with O-acyl greatly reduced the inhibitory potency, which tended to increase upon replacement of both phosphate moieties of the acyclic derivatives with uncharged (e.g., ester) groups. In the series of nonsymmetrically substituted monophosphates, the optimal antagonist potency occurred with the phenylcarbamate group. Among symmetrical diester derivatives, the optimal antagonist potency occurred with the di(phenylacetyl) group. A dipivaloyl derivative, a representative uncharged diester, inhibited ADP-induced aggregation in both rat (KI 3.6 μM) and human platelets. It antagonized the ADP-induced inhibition of the cyclic AMP pathway in rat platelets (IC50 7 μM) but did not affect hP2Y1 receptor-induced PLC activity measured in transfected astrocytoma cells. We propose that the uncharged derivatives are acting as antagonists of a parallel pro-aggregatory receptor present on platelets, that is, the P2Y12 receptor. Thus, different substitution of the same nucleoside scaffold can target either of two P2Y receptors in platelets.
Xu, Bin,Stephens, Andrew,Kirschenheuter, Gary,Greslin, Arthur F.,Cheng, Xiaoquin,Sennelo, Joe,Cattaneo, Marco,Zighetti, Maddalena L.,Chen, Aishe,Kim, Soon-Ai,Kim, Hak Sung,Bischofberger, Norbert,Cook, Gary,Jacobson, Kenneth A.
p. 5694 - 5709
(2007/10/03)

3-Acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid as novel vanilloid receptor agonists
A series of 3-acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid were designed and synthesized as vanilloid receptor agonists containing the three principal pharmacophores of resiniferatoxin. Amide analogues 23, 5 and 11 were found to be potent agonists in vanilloid receptor assay both for ligand binding and for activation.
Lee, Jeewoo,Park, Shin-Ung,Kim, Ji-Young,Kim, Jin-Kwan,Lee, Jiyoun,Oh, Uhtaek,Marquez, Victor E.,Beheshti, Maryam,Wang, Qiming J.,Modarres, Shayan,Blumberg, Peter M.
p. 2909 - 2914
(2007/10/03)

Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design
A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, his tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein- ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.
Melnick, Michael,Reich, Siegfried H.,Lewis, Kathy K.,Mitchell Jr., Lennert J.,Nguyen, Dzuy,Trippe, Anthony J.,Dawson, Heather,Davies II, Jay F.,Appelt, Krzysztof,Wu, Bor-Wen,Musick, Linda,Gehlhaar, Dan K.,Webber, Stephanie,Shetty, Bhasker,Kosa, Maha,Kahil, Deborah,Andrada, Dominic
p. 2795 - 2811
(2007/10/03)

Synthetic studies on spiroketal natural products. IV. A stereoselective synthesis of (3S,5S,6R,9R,R(S))-3-benzyloxymethyl-9-hydroxymethyl-5-(p-tolyl)sulfin yl-1,7-dioxaspiro[5.5]undecane, a key intermediate for talaromycins
A dioxaspiro compound (4), a common intermediate for the synthesis of talaromycin A (1) and (-)-talaromycin B (2), was synthesized by two routes utilizing two kinds of asymmetric recognition of prochiral 1,3-diols controlled by sulfinyl chirality, that is, firstly by acid promoted diastereoselective C-O bond fission of the bicyclic acetal (7) to give the dihydropyran derivative (6), which has an S-hydroxymethyl group at the C3-position (7 → 6), and secondly by diastereoselective intramolecular Michael addition of the diol (5), in which the three chiral centers at C5, C6, C9 were constructed in one step (5 → 4).
Iwata,Maezaki,Hattori,Fujita,Moritani,Takemoto,Tanaka,Imanishi
p. 339 - 345
(2007/10/02)

SYNTHESIS OF 5,5'-DIHYDROXYLEUCINE AND 4-FLUORO-5,5'-DIHYDROXYLEUCINE, THE REDUCTION PRODUCTS OF 4-CARBOXYGLUTAMIC AND 4-CARBOXY-4-FLUOROGLUTAMIC ACIDS
Schemes for the synthesis of 5,5'-dihydroxyleucine 3 and its 4-fluoro analog 7 involving the condensation of a suitable 'aminoacid moiety' with 2,2-dimethyl-5-iodomethyl-1,3-dioxane 15D or its fluoro analog 27A were tested.The anion of the ethyl N-diphenylmethylene-glycinate 25 gave better yields of 3 than the classical anion of diethyl acetamidomalonate.This strategy could not be successfully applied to the synthesis of 7, which could be prepared by reduction of a suitably protected 4-fluoro-4-carboxyglutamate with BMS.
Dubois, Joelle,Foures, Christine,Bory, Sonia,Falcou, Serge,Gaudry, Michel,Marquet, Andree
p. 1001 - 1012
(2007/10/02)

Synthesis and antiviral activity of 9-alkoxypurines. 1. 9-(3-Hydroxypropoxy)- and 9-[3-hydroxy-2-(hydroxymethyl)propoxy]purines
Reaction of hydroxyl-protected derivatives of hydroxyalkoxyamines (3a,b,c) with either 4,6-dichloro-2,5-diformamidopyrimidine (5) or 4,6-dichloro-5-formamidopyrimidine (31) and subsequent cyclization of the resultant 6-(alkoxyamino)pyrimidines (6, 17, 32, 35) by heating with diethoxymethyl acetate afforded 9-alkoxy-6-chloropurines (7, 18, 33, 36), which were converted subsequently to 9-(3-hydroxypropoxy)- and 9-[3-hydroxy-2-(hydroxymethyl)propoxy] derivatives of guanine, 2-amino-6-chloropurine, 2-amino-6-alkoxypurines, 2-aminopurine, 2,6-diaminopurine, adenine, hypoxanthine, and 6-methoxypurine (8, 12, 13, 19-21, 23-26, 34, 37-39). Carboxylic acid esters (9-11, 14-16, 27-29) and a cyclic phosphate derivative (22) of the 9-(hydroxyalkoxy)guanines (8, 21) and 2-amino-9-(hydroxyalkoxy)purines (13, 26) were also prepared. The guanine derivatives (8, 21) showed potent and selective activity against herpes simplex virus types 1 and 2 and varicella zoster virus in cell cultures and 8 is more active than acyclovir. Although without significant antiviral activity in cell cultures, the 2-aminopurines (13, 14-16, 26-29) and 2-amino-6-alkoxypurines (12, 23-25) are well absorbed after oral administration to mice and are converted efficiently to the antiviral guanine derivatives (8, 21) in vivo.
Harnden,Wyatt,Boyd,Sutton
p. 187 - 196
(2007/10/02)

Synthesis and Evaluation of Phospholipid Analogues as Inhibitors of Cobra Venom Phospholipase A2
Analogues of phospholipids that contain fluoro ketone, ketone, and alcohol replacements for the ester at the 2-position of the glycerol backbone have been prepared and analyzed as inhibitors of phospholipase A2 from Naja naja naja venom.Phospholipid analogues were studied that contain two alkyl chains as well as single chain compounds that lack carbon-1 of the glycerol backbone and the attached acyl unit.Compounds that contain both long and medium length alkyl chains were studied.All of the potential inhibitors were tested in a well-defined mixed micelle system in which both the substrates and the inhibitors have been incorporated into Triton X-100 micelles.Surprisingly, the best inhibitors studied were the single chain fluoro ketones despite the fact that the enzyme has a strong preference for two-chain lipids.The most potent compound was found to have a dissociation constant some 600-3000-fold lower than the Michaelis constant for dipalmitoyl phosphatidylcholine substrate. 19F NMR studies of the fluoro ketone phospholipid analogues in micelles show that whereas the single chain compounds are partially in the hydrated-ketone form, the two-chain compounds are less than 0.1percent hydrated.In every case studied, potent inhibition of phospholipase A2 was observed only with those compounds that are significantly hydrated in the micelle, and it is suggested that the hydrated fluoro ketone containing phospholipid analogues are the species responsible for the inhibition.In addition, the single chain fluoro ketones were better inhibitors than single and double chain alcohol and ketone analogues.Previous studies have been show that the cobra venom enzyme is activated by choline-containing lipids, and evidence is presented for the binding of the hydrated fluoro ketone inhibitors selectively to the activated enzyme.
Yuan, Wei,Berman, Richard J.,Gelb, Michael H.
p. 8071 - 8081
(2007/10/02)

An Approach to Pseudomonic Acids from Acetylenic Precursors: Synthesis of 2-(Hydroxymethyl)-3-butyn-1-ol
The acetonide of 2-(hydroxymethyl)-3-butyn-1-ol (17) was prepared from bis(hydroxymethyl)malonate (11) or from 1,3-dihydroxypropanone (22).Alternative routes to 17 involving the intermediacy of highly unstable alkynal 21 or the corresponding acetate were unsuccessful.Condensation of the anion of 17 with aldehyde 30 followed by semihydrogenation and deprotection afforded keto triol 33, which cyclized stereoselectively to dihydropyran 34.Osmylation and functional group manipulation afforded 40 and 42, precursors to pseudomonic acid C (1).
Bates, Hans Aaron,Farina, James,Tong, Michael
p. 2637 - 2641
(2007/10/02)

2-Hydroxymethyl-1,3-propanediol preparation
2-Hydroxymethyl-1,3-propanediol trinitrate, processes for its preparation, and compounds related thereto are disclosed. The final product is useful as a plasticizer of relatively low volatility in double based propellant compositions and as a liquid explosive.
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(2008/06/13)