- Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon
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Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.
- Caiger, Lewis,Constantin, Timothée,Douglas, James J.,Juliá, Fabio,Leonori, Daniele,Sheikh, Nadeem S.,Sinton, Conar
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p. 10448 - 10454
(2021/08/20)
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- X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
- Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
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p. 8303 - 8332
(2021/06/30)
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- TRPML MODULATORS
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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- A process for preparing N - Boc - 3 - pyrrolidine of formaldehyde (by machine translation)
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The invention discloses a method for preparing N - Boc - 3 - pyrrolidine of formaldehyde, comprising the following steps: (1) in the solvent is added in chloromethane-based [...] and triphenyl phosphate reaction, to obtain the benzyloxy methyl trityl chloride; (2) the benzyloxy methyl trityl chloride by adding solvent, under alkaline conditions, adding N - Boc - 3 - pyrrolidone reaction, to obtain compound N - Boc - 3 - benzyloxy methylene pyrrolidine; (3) high-pressure container for adding a solvent, N - Boc - 3 - benzyloxy methylene pyrrolidine and catalyst, hydrogenation reaction to obtain N - Boc - 3 - pyrrolidine methanol; (4) will be N - Boc - 3 - pyrrolidine methanol dissolved in dichloromethane solvent, adding Dess - Martin oxidizer to carry out oxidizing, get N - Boc - 3 - pyrrolidine formaldehyde. The method of the invention has the following advantages: the used raw materials low toxicity, easy, low cost, consumption, high yield, few by-products, easy large-scale production. (by machine translation)
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Paragraph 0045; 0048; 0050; 0053
(2019/02/04)
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- Method for synthesizing N-Boc-3-pyrrolidine formaldehyde
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The invention discloses a method for synthesizing N-Boc-3-pyrrolidine formaldehyde. The method comprises that dimethyl itaconate as a raw material undergoes an intramolecular cyclization reaction to produce methyl 5-oxo-3-pyrrolidine carboxylate, then the methyl 5-oxo-3-pyrrolidine carboxylate undergoes a reduction reaction to produce pyrrolidine-3-methanol, then the pyrrolidine-3-methanol is subjected to Boc protection so that N-Boc-pyrrolidine-3-methanol is obtained, and finally, the N-Boc-pyrrolidine-3-methanol is oxidized to form a final product compound. The method is simple and convenient, has a low cost, content greater than 99%, produces small environmental pollution and is suitable for industrial production.
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- A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790Mmutant with improved pharmacokinetic properties
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Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790Minhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790Mkinase and inhibited the proliferation of H1975?cells with IC50values of 2.0?nM and 40?nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCI[sbnd]H1975?cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.
- Yu, Lei,Huang, Minhao,Xu, Tianfeng,Tong, Linjiang,Yan, Xiao-e,Zhang, Zhang,Xu, Yong,Yun, Caihong,Xie, Hua,Ding, Ke,Lu, Xiaoyun
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supporting information
p. 1107 - 1117
(2016/12/30)
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- Enantioselective Fluorination of Spirocyclic β-Prolinals Using Enamine Catalysis
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A series of spirocyclic carbaldehydes were successfully fluorinated using enamine catalysis, furnishing the corresponding tertiary fluorides in both high yields and enantioselectivities. The fluorinated spirocycles provide a set of novel building blocks interesting from a medicinal chemistry point of view.
- Fjelbye, Kasper,Marigo, Mauro,Clausen, Rasmus Pr?torius,Juhl, Karsten
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supporting information
p. 425 - 428
(2017/02/24)
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- Preparation method of 1-BOC-3-hydroxymethyl pyrrolidine
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The invention discloses a preparation method of 1-Boc-3-hydroxymethyl pyrrolidine. The preparation method uses epichlorohydrin as a raw material, 3-hydroxymethyl pyrrolidine is obtained through reduction and cyclization reaction, then the 1-Boc-3-hydroxymethyl pyrrolidine is prepared through Boc protection reaction, then 1-BOC-3-methyl formate pyrrolidine is prepared through carboxylation reaction and esterification reaction, and finally the 1-BOC-3-methyl formate pyrrolidine and lithium aluminum hydride are catalyzed by a catalyst to prepare the 1-BOC-3-hydroxymethyl pyrrolidine. The preparation method is high in product synthesis rate, high in product purity and low in production cost, and the raw materials are cheap and easy to obtain.
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- POLYFLUORINATED COMPOUNDS ACTING AS BRUTON TYROSINE KINASE INHIBITORS
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Described herein is a novel series of multi-fluoro-substituted pyrazolopyrimidine compounds or salts thereof. These compounds are Bruton's tyrosine kinase (BTK) inhibitors. These compounds may possess better BTK inhibition selectivity and pharmacokinetic properties. Disclosed herein are the synthesis methods of these compounds. Disclosed herein are novel synthesis methods of the multi-fluoro-substituted benzophenone and substituted phenoxy benzene. Also disclosed are pharmaceutical compositions comprising the BTK inhibitors described herein. The present invention also relates to pharmaceutical formulations comprising the compounds described herein as active ingredients. The present invention also includes the therapeutic methods by administering the BTK inhibitors and their formulations to treat and inhibit autoimmune disease, hypersensitivity disease, inflammatory diseases and cancer.
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Paragraph 0405; 0406
(2016/08/17)
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- HETEROCYCLIC COMPOUNDS AS NAV CHANNEL INHIBITORS AND USES THEREOF
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The present invention relates to heterocyclic compounds of formula (I) wherein: Z1 is C(R)(R), C(O), C(S), or C(NR); 2 Z is C(R)(R), 0, S, SO, S02, or NR; X is -O-, -S-, -S02-, -SO-, -C(O)-, -C02-, -C(O)N(R)-, -NRC(O)-, -NRC(O) N(R)-, -NRSO2-, or -N(R)-; or X is absent; A is an optionally substituted C1_6 aliphatic, C5-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocylic ring, or a 5-6 membered heteroaryl ring; Y is -CH2-, -O-, -S-, -S02-, -SO-, -C(O)-, -C02-, -C(O)N(R)-, -NRC(O)-, - NRC(O)N(R)-, -NRS02-, or -N(R)-; B is an optionally substituted C5-10 aryl or 5-6 membered heteroaryl ring; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and r is 1 or 2; and pharmaceutically acceptable compositions thereof, useful as Navl.6 inhibitors.
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Paragraph 00173
(2015/09/28)
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- MULTIPLE KINASE PATHWAY INHIBITORS
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Kinase with inhibitory activity against kinases disposed in multiple signaling pathways and their therapeutic uses.
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Page/Page column 239-241
(2014/04/17)
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- Ruthenium-catalyzed hydroformylation/reduction of olefins to alcohols: Extending the scope to internal alkenes
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In the presence of 2-phosphino-substituted imidazole ligands and Ru 3(CO)12 or Ru(methylallyl)2(COD) direct hydroformylation and hydrogenation of alkenes to alcohols takes place. In addition to terminal alkenes, also more challenging internal olefins are converted preferentially to industrially important linear alcohols in high yield (up to 88%) and regioselectivity (n:iso up to 99:1).
- Wu, Lipeng,Fleischer, Ivana,Jackstell, Ralf,Profir, Irina,Franke, Robert,Beller, Matthias
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supporting information
p. 14306 - 14312
(2013/10/21)
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- PYRIDINE AMIDE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
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The invention relates pyridine amide derivative of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, linear o branched (C1-C3)alkyl or joined together they form a cyclopropyl ring; R is independently selected from the group consisting of halogens and trifluoromethyl and p is 1, 2 or 3; A is C or N; E is a group of formula (B) or (C), wherein B is C(O)OH, C(O)O(C1-C3)alkyl, and C is selected from the group consisting of formula (I) m is 1,2 or 3, n is 0 or 1, W is —O—, —O(C1-C3 alkyl)-; —(C1-C3 alkyl)O—; —C(O)—; —C(═N—O(C1-C3 alkyl))-; —NH— or —NH(C1-C3alkyl)-; Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, —NH(C1-C3alkyl)-; —N(C1-C3alkyl)(C1-C3alkyl)-, a from 5 to 7 membered heterocyclic ring containing one nitrogen atom which is covalently bonded to Ar and optionally containing one or two heteroatoms selected from N, O and S; and a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, such heteroaromatic ring being substituted with one or two substituents selected from the group consisting of (C1-C3)alkyl, (C3-C5)cycloalkyloxy, (C1-C3)alkylcarbonyl. The compounds of the invention could be used for manufacturing a medicament for the treatment of pathologies which require the use of an antagonist of the EP4 receptor, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, endometriosis and migraine.
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Paragraph 0387-0388
(2013/10/08)
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- PYRIDINE AMIDE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
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The invention relates pyridine amide derivative of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, linear o branched (C1-C3)alkyl or joined together they form a cyclopropyl ring; R is independently selected from the group consisting of halogens and trifluoromethyl and p is 1, 2 or 3; A is C or N; E is a group of formula (B) or (C), wherein B is C(O)OH, C(O)O(C1-C3)alkyl, and C is selected from the group consisting of formula (I) m is 1,2 or 3, n is 0 or 1, W is -O-, -O(C1-C3 alkyl)-; -(C1-C3 alkyl)O-; -C(O)-; -C(=N-O(C1-C3 alkyl))-; -NH- or -NH(C1-C3alkyl)-; Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, -NH(C1-C3alkyl)-; -N(C1-C3alkyl)(C1-C3alkyl)-, a from 5 to 7 membered heterocyclic ring containing one nitrogen atom which is convalently bonded to Ar and optionally containing one or two heteroatoms selected from N, O and S; and a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, such heteroaromatic ring being substituted with one or two substituents selected from the group consisting of (C1-C3)alkyl, (C3-C5)cycloalkyloxy, (C1-C3)alkylcarbonyl. The compounds of the invention could be used for manufacturing a medicament for the treatment of pathologies which require the use of an antagonist of the EP4 receptor, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid artrhritis, cancer, endometriosis and migraine.
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Page/Page column 54
(2012/06/30)
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- PICOLINAMIDE DERIVATIVES AS TTX-S BLOCKERS
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The present invention relates to picolinamide derivatives which have blocking activities of voltage gated sodium channels as the TTX-S channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.
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Page/Page column 92
(2011/02/24)
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- ARYLOXYALKYLCARBAMATE-TYPE DERIVATIVES, PREPARATION METHOD THEREOF AND USE OF SAME IN THERAPEUTICS
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The invention relates to a compound of formula (I): [image] Wherein m, n, X, Y, R1, R2, R3 and R4 are as defined herein. The invention also relates to the use of same in therapeutics.
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Page/Page column 10
(2008/06/13)
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- QUINOLONE ANTIBACTERIAL AGENTS
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Compounds of formula (I) wherein A is formula (II), formula (III) or formula (IV), and B is formula (V), formula (VI), or formula (VII), can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 89; 90; 130; 131
(2010/02/12)
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- ANTIBACTERIAL AMINOQUINAZOLIDINEDIONE DERIVATIVES
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Compounds of formula (I) wherein: A is Formula (II), Formula (III), or Formula (IV) and B is Formula (V), Formula (VI), or Formula (VII), can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 117; 118; 158; 159
(2010/02/12)
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- Design and synthesis of potent, orally active, inhibitors of carboxypeptidase U (TAFIa)
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A series of 3-mercapto-propionic acid derivatives that function as reversible inhibitors of carboxypeptidase U have been prepared. We present a successful design strategy using cyclic, low basicity guanidine mimetics resulting in potent, selective and bioavailable inhibitors of carboxypeptidase U (TAFIa).
- Polla, Magnus O.,Tottie, Louise,Norden, Carita,Linschoten, Marcel,Muesil, Djordje,Trumpp-Kallmeyer, Susanne,Aukrust, Inger R.,Ringom, Rune,Holm, Kjetil H.,Neset, Siren M.,Sandberg, Marcel,Thurmond, John,Yu, Peng,Hategan, Georgeta,Anderson, Herb
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p. 1151 - 1175
(2007/10/03)
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- Beta lactam compounds and their use as inhibitors of tryptase
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Beta lactam compounds are provided which have the structure wherein B, A, D, R1, R2, R3 and X1 are as defined herein, and which are useful as inhibitors of tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, and urokinase-type plasminogen activator and may be employed in preventing and/or treating asthma and allergic rhinitis.
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Page/Page column 36-37
(2010/02/07)
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- Pyridine derivatives
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Pyridine compounds of general formula: wherein —R1represents in which R11is hydrogen, C1-6alkyl, halogen, hydroxy, C1-12alkoxy, nitro, amino, C1-6alkylsulfonylamino, C1-6alkoxycarbonyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkanoylamino, phenyl C1-6alkylamino, phenylsulfonylamino, or —O—(CH2)n—R111; R2represents hydrogen or halogen; R3represents hydrogen, —CR31R32R33, or —NR34R35; R4is hydrogen, carbamoyl, CN, carboxyl, etc.; R5is amino, C1-6alkylamino, di C1-6alkylamino, etc. or salt thereof. The compound has an excellent anti-inflammatory activity, and other biological activity.
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- Cathepsin cysteine protease inhibitors
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This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of Cathepsins K and L. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
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- Synthesis of potent and highly selective inhibitors of human tryptase
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The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC503000-fold) for tryptase versus related serine proteases including trypsin.
- Slusarchyk, William A.,Bolton, Scott A.,Hartl, Karen S.,Huang, Ming-Hsing,Jacobs, Glenn,Meng, Wei,Ogletree, Martin L.,Pi, Zulan,Schumacher, William A.,Seiler, Steven M.,Sutton, James C.,Treuner, Uwe,Zahler, Robert,Zhao, Guohua,Bisacchi, Gregory S.
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p. 3235 - 3238
(2007/10/03)
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- CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships.
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CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
- Wacker, Dean A,Santella 3rd., Joseph B,Gardner, Daniel S,Varnes, Jeffrey G,Estrella, Melissa,DeLucca, George V,Ko, Soo S,Tanabe, Keiichi,Watson, Paul S,Welch, Patricia K,Covington, Maryanne,Stowell, Nicole C,Wadman, Eric A,Davies, Paul,Solomon, Kimberly A,Newton, Robert C,Trainor, George L,Friedman, Steven M,Decicco, Carl P,Duncia, John V
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p. 1785 - 1789
(2007/10/03)
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- Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L
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Compounds containing a 1-cyanopyrrolidinyl ring were identified as potent and reversible inhibitors of cathepsins K and L. The original lead compound 1 inhibits cathepsins K and L with IC50 values of 0.37 and 0.45 μM, respectively. Modification of compound 1 by replacement of the quinoline moiety led to the synthesis of N-(1-cyano-3-pyrrolidinyl)benzenesulfonamide (2). Compound 2 was found to be a potent inhibitor of cathepsins K and L with a Ki value of 50 nM for cathepsin K. Replacement of the 1-cyanopyrrolidine of compound 2 by a 1-cyanoazetidine increased the potency of the inhibitor by 10-fold. This increase in potency is probably due to an enhanced chemical reactivity of the compound toward the thiolate of the active site of the enzyme. This is demonstrated when the assay is performed in the presence of glutathione at pH 7.0 which favors the formation of a GSH thiolate anion. Under these assay conditions, there is a loss of potency in the 1-cyanoazetidine series due to the formation of an inactive complex between the GSH thiolate and the 1-cyanoazetidine inhibitors. 1-Cyanopyrrolidinyl inhibitors exhibited time-dependent inhibition which allowed us to determine the association and dissociation rate constants with human cathepsin K. The kinetic data obtained showed that the increase of potency observed between different 1-cyanopyrrolidinyl inhibitors is due to an increase of kon values and that the association of the compound with the enzyme fits an apparent one-step mechanism. 13C NMR experiments performed with the enzyme papain showed that compound 2 forms a covalent isothiourea ester adduct with the enzyme. As predicted by the kinetic analysis, the addition of the irreversible inhibitor E64 to the enzyme-cyanopyrrolidinyl complex totally abolished the signal of the isothiourea bond as observed by 13C NMR, thereby demonstrating that the formation of the covalent bond with the active site cysteine residue is reversible. Finally, compound 2 inhibits bone resorption in an in vitro assay involving rabbit osteoclasts and bovine bone with an IC50 value of 0.7 μM. 1-Cyanopyrrolidine represents a new class of nonpeptidic compounds that inhibit cathepsin K and L activity and proteolysis of bone collagen.
- Falgueyret,Oballa,Okamoto,Wesolowski,Aubin,Rydzewski,Prasit,Riendeau,Rodan,Percival
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- Quinoline-3-carboxylic acid derivatives
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Compounds of formula (I): STR1 (in which R1 is alkoxy, R is alkyl, haloalkyl, alkylamino, cycloalkyl or optionally substituted phenyl, X is chlorine or fluorine and Y is selected from certain specific heterocycles) have excellent antibacterial activity. They may be prepared by introducing the group represented by Y into the corresponding compound in which Y is replaced by a halogen atom.
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