- Immunoregulator
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The invention discloses an immune regulator, in particular to a compound for inhibiting IL - 17A and application of the compound as an immunomodulator in preparation of medicines. The invention discloses a compound shown in formula I. The application of t
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Paragraph 0119; 0126-0128
(2021/11/26)
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- Membrane-active antimicrobial poly(amino-modified alkyl) β-cyclodextrins synthesized: Via click reactions
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The emergence of drug-resistant bacteria has led to the high demand for new antibiotics. In this report, we investigated membrane-active antimicrobial β-cyclodextrins. These contain seven amino-modified alkyl groups on a molecule, which act as functional
- Yamamura, Hatsuo,Nonaka, Miho,Okuno, Shingo,Mitsuhashi, Ryogo,Kato, Hisato,Katsu, Takashi,Masuda, Kazufumi,Tanimoto, Koichi,Tomita, Haruyoshi,Miyagawa, Atsushi
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p. 509 - 518
(2018/03/26)
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- Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes
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Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive r
- De Bruin, Gerjan,Huber, Eva M.,Xin, Bo-Tao,Van Rooden, Eva J.,Al-Ayed, Karol,Kim, Kyung-Bo,Kisselev, Alexei F.,Driessen, Christoph,Van Der Stelt, Mario,Van Der Marel, Gijsbert A.,Groll, Michael,Overkleeft, Herman S.
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supporting information
p. 6197 - 6209
(2014/08/18)
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- COMPOUNDS AND COMPOSITIONS AS CHANNEL ACTIVATING PROTEASE INHIBITORS
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The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating channel activating proteases, and methods for using such compounds to treat, ameliorate or prevent a condition associated with a channel activating protease, including but not limited to prostasin, PRSS22, TMPRSS11 (e.g., TMPRSS11B, TMPRSS11E), TMPRSS2, TMPRSS3, TMPRSS4 (MTSP-2), matriptase (MTSP-1), CAP2, CAP3, trypsin, cathepsin A, or neutrophil elastase.
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Page/Page column 32
(2008/12/08)
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- A direct and efficient stereoconservative procedure for the selective oxidation of N-protected β-amino alcohols
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An efficient, very simple and eco-friendly procedure has been developed for the synthesis of highly enantioenriched α-amino aldehydes by IBX-mediated oxidation of the corresponding β-amino alcohols. The procedure has been applied to a wide range of substr
- Ocejo, Marta,Vicario, Jose L.,Badía, Dolores,Carrillo, Luisa,Reyes, Efraim
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p. 2110 - 2112
(2007/10/03)
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- Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy
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Dipeptide-derived α-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC50 values down to 25 nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.
- Lescop, Cyrille,Herzner, Holger,Siendt, Herve,Bolliger, Reto,Henneboehle, Marco,Weyermann, Philipp,Briguet, Alexandre,Courdier-Fruh, Isabelle,Erb, Michael,Foster, Mark,Meier, Thomas,Magyar, Josef P.,Von Sprecher, Andreas
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p. 5176 - 5181
(2007/10/03)
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- Exploration of the P1 SAR of aldehyde cathepsin K inhibitors.
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The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.
- Catalano, John G,Deaton, David N,Furfine, Eric S,Hassell, Annie M,McFadyen, Robert B,Miller, Aaron B,Miller, Larry R,Shewchuk, Lisa M,Willard Jr., Derril H,Wright, Lois L
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p. 275 - 278
(2007/10/03)
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- Novel, potent and selective chimeric FXa inhibitors featuring hydrophobic P1-ketoamide moieties
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Judicious combination of P-region sequences of highly potent anticoagulant proteins including NAP5, NAP6, Ecotin, and Antistasin with SAR from small molecule FXa inhibitors led to a series of chimeric inhibitors of formula 1a-j. We report herein the desig
- Semple,Levy, Odile E.,Minami, Nathaniel K.,Owens, Timothy D.,Siev, Daniel V.
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p. 2305 - 2309
(2007/10/03)
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- Difluoro ketone peptidomimetics suggest a large S1 pocket for Alzheimer's γ-secretase: Implications for inhibitor design
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The final step in the generation of the amyloid-β protein (Aβ), implicated in the etiology of Alzheimer's disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by γ-secretase. Although considered an important target for therapeutic design, γ-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alcohol transition-state analogue inhibitors suggest that γ-secretase is an aspartyl protease with loose sequence specificity. To further characterize the active site of γ-secretase, we prepared a series of difluoro ketone peptide analogues with varying steric bulkiness in the P1 position and tested the ability of these compounds to inhibit Aβ production in APP-transfected cells. Incorporation of bulky, aliphatic P1 side chains, such as sec-butyl or cyclohexylmethyl, led to increased α-secretase inhibitory potency, suggesting a large S1 pocket to accommodate these substituents and providing further evidence for loose sequence specificity. The cyclohexylmethyl P1 substituent allowed N-terminal truncation to a low-molecular-weight compound (50 ~ 5 μM). This finding suggests that optimal S1 binding may allow the development of potent inhibitors with ideal pharmaceutical properties. Moreover, a difluoro alcohol analogue with a cyclohexylmethyl P1 substituent was equipotent with its difluoro ketone counterpart, providing strong evidence that γ-secretase is an aspartyl protease. All new analogues inhibited total Aβ and Aβ42 production with the same rank order of potency and increased Aβ42 production at low concentrations, providing further evidence for distinct γ-secretases that are nevertheless closely similar with respect to active site topology and mechanism.
- Moore,Leatherwood,Diehl,Selkoe,Wolfe
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p. 3434 - 3442
(2007/10/03)
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- Stereoselective intramolecular cyclization of allyl and homoallyl benzamide via π-allylpalladium complex catalyzed by Pd(0)
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The transformation of acyclic allylic benzamides 4 and homoallylic benzamides 12 to vinyl oxazolines 3 is achieved in the presence of base by the catalysis and Pd(0) in high yield and with high diastereoselectivity. Especially, in the case of homoallylic benzamides 12, trans-oxazolines 3 are formed exclusively or predominantly over cis-oxazolines 8, irrespective of the composition of their stereoisomers. The reaction is believed to proceed via the same π-allylpalladium complex that arises from either primary or secondary allylic acetates. We applied this method to the syntheses of β- amino-α-hydroxy acids 1 and γ-amino-β-hydroxy acids 2, conveniently protected as oxazoline.
- Lee, Kee-Young,Kim, Yong-Hyun,Park, Min-Sung,Oh, Chang-Young,Ham, Won-Hun
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p. 9450 - 9458
(2007/10/03)
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- Potent and Selective Inhibitors of an Aspartyl Protease-like Endothelin Converting Enzyme Identified in Rat Lung
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Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed.Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series.Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity.Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity.Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D.Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing.Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.
- Shiosaki, Kazumi,Tasker, Andrew S.,Sullivan, Gerard M.,Sorensen, Bryan K.,Geldern, Thomas W. von,et al.
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p. 468 - 478
(2007/10/02)
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- THE SYNTHESIS OF HETEROCYCLIC C-TERMINAL UNITS WHICH MIMIC THE TRANSITION STATE IN THE CLEAVAGE OF THE LEU-VAL BOND OF ANGIOTENSINOGEN BY RENIN
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The stereospecific synthesis of (S)2-amino-3-cyclohexyl-(R)1-(2-furanyl)-propan-1-ol (17) and (S)2-amino-3-cyclohexyl-(R)1-(2-thienyl)-propan-1-ol (18) from t-Boc-L-phenylalanine is described.Reduction of the furan ring of (4S-trans)-4-(cyclohexylmethyl)-
- Albright, J. Donald,Howell, Charles F.,Sum, F. W.
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p. 737 - 754
(2007/10/02)
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- Activated ketone based inhibitors of human renin
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Application of the concept of activated ketones to the design of novel and potent transition-state analog inhibitors of the aspartyl protease renin is described. Three different classes of peptidic activated ketones were synthesized: 1,1,1-trifluoromethyl ketones, α-keto esters, and α-diketones. The corresponding alcohols were also evaluated as renin inhibitors in each series. While the trifluoromethyl alcohol 12 (I50 = 4000 nM) was equipotent to the simple methyl alcohol 7 (I50 = 3200 nM), the structurally similar α-hydroxy esters (32 and 30, I50's = 5.3 and 4.7 nM, respectively) and α- hydroxy ketones (41 and 42, I50 = 23 and 15 nM, respectively) were 150- 300-fold more active. The hydrating capability of the activated ketone functionality was important for intrinsic potency in the case of trifluoromethyl ketones, as illustrated by the significantly better activity of trifluoromethyl ketone 13 (I50 = 250 nM) compared to its alcohol analog 12 (I50 = 4000 nM). It was however unimportant for the α-keto ester (20 and 31, I50 = 15 and 4.1 nM, respectively) and α-diketone (43 and 44, I50 = 52 and 28 nM, respectively) based inhibitors, since their activity was essentially similar to that of the corresponding alcohols. These results collectively suggest that, whereas the trifluoromethyl ketones derive their renin inhibitory potency primarily from their ability to become hydrated, this is not a critical feature for the activity of α-dicarbonyl-based inhibitors. The α-keto ester and α-diketone based renin inhibitors benefit predominantly from the hydrophobic and/or H-bonding type binding interactions of the neighboring ester or acyl group itself, rather than the ability of this group to deactivate the adjacent ketone group and thereby make it susceptible to hydration.
- Patel,Rielly-Gauvin,Ryono,Free,Smith,Petrillo Jr.
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p. 2431 - 2447
(2007/10/02)
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- Synthesis of α-amino and α-alkoxy aldehydes via oxoammonium oxidation
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Oxoammonium oxidation (TEMPO, 1) of various optically active α-amino and α-alkoxy alcohols affords the corresponding aldehydes in good yield and high enantiomeric purity.
- Leanna,Sowin,Morton
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p. 5029 - 5032
(2007/10/02)
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- Synthesis of the hydroxyethylene dipeptide isostere, (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid n-butyl amide
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A stereoselective synthesis of the hydroxyethylene dipeptide isostere, (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid-n-butyl amide from Boc-L-phenylalanine is described.
- Poss,Reid
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p. 1411 - 1414
(2007/10/02)
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- DIOL SULFONAMIDE AND SULFINYL RENIN INHIBITORS
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Compounds of the formula STR1 wherein Z is SO or SO 2 possess renin inhibition activity and are useful in treating hypertension and other diseases where the reduction of the levels of circulating angiotensin II are beneficial.
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- Orally Potent Human Renin Inhibitors Derived from Angiotensinogen Transition State: Design, Synthesis, and Mode of Interaction
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A three-dimensional structure of the complex of human renin and the scissile site P4 Pro to P1' Val of angiotensinogen was deduced in order to design potent human renin inhibitors rationally.On the basis of this structure, an orally
- Iizuka, Kinji,Kamijo, Tetsuhide,Herada, Hiromu,Akahane, Kenji,Kubota, Tetsuhiro,et al.
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p. 2707 - 2714
(2007/10/02)
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- Synthesis of 6(S)-Amino-7-cyclohexyl-4,4-difluoro-3(R),5(R)-dihydroxy-2-methylheptane, a Novel Dipeptide Mimic
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The incorporation of the novel dipeptide mimic (1), synthesized via Boc-L-cyclohexylalaninol (Boc = t-butoxycarbonyl), into a dipeptide sequence has led to a very potent renin inhibitor.
- Sham, Hing L.,Rempel, Cheryl A.,Stein, Herman,Cohen, Jerome
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p. 904 - 905
(2007/10/02)
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- Novel amino acid derivatives possessing renin-inhibitory activities
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An amino acid derivative of the general formula: wherein, R1? is a lower alkyl group and R11 is (wherein R111 is a lower alkyl group and n is an integer of 1 to 5) or a lower alkyl group which may be substituted by hydroxy group or methoxyethoxymethoxy group, or R1? and R11 are combinedly together with the adjacent nitrogen atom; R12 is a hydrogen atom, CnH2n+ 1-O-CO-(n is as defined above) or R13 is a lower alkyl group which may be substituted by substituent(s) selected from HOOC-(H?C)n-O-, R12-NH-(n and R12 are as defined above) and pyridyl group; X is-CH?-,-O-or-NH-and Y is-O-or-NH-; wherein (wherein Z is-O-,-S-,-S(O)-,-S(O)?-,-CH?-,-CH(OH)-,---,-NH-or and a and b are independently an integer of 1 to 4 and the total of a and b is not more than 5) ; R2 is an aralkyl group which may be substituted by lower alkyl group(s); R3 is a hydrogen atom or a lower alkyl group; R? is a lower alkyl group; and A is hydroxy group and B is a hydrogen atom, or A and B are carbonyl group combinedly together with the adjacent carbon atom, a pharmaceutically acceptable acid addition salt or an ester thereof is described. The compounds of the invention possess inhibitory activities against renin and are useful as an antihypertensive agent.
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- Renin inhibitors containing 5-amino-2,5-disubstituted-4-hydroxypentanoic acid residues
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A series of novel polypeptide derivatives, containing 5-amino-2,5-disubstituted-4-hydroxypentanoic acid residues, which are useful for inhibiting the angiotensinogen-cleaving action of the enzyme renin. Particularly valuable precursors for many of these compounds are certain other 5-amino-2,5-disubstituted-4-hydroxypentanoic acid derivatives.
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- Renin Inhibitors. Syntheses of Subnanomolar, Competitive, Transition-State Analogue Inhibitors Containing a Novel Analogue of Statine
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Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin.Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3s,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), gave the most potent inhibitors of renin yet reported, including N-isovaleryl-L-histydyl-L-prolyl-L-phenylalanyl-L-histydyl-ACHPA-L-leucyl-L-phenylalanyl amide , with renin inhibitions of Ki=1.6 * 10-10 M (human kidney renin), IC50=1.7 * 10-10 M (human plasma renin), IC50=1.9 * 10-9 M (dog plasma renin), and IC50=2.1 * 10-8 M (rat plasma renin).This inhibitor 3, containing ACHPA, was 55-76 times more potent vs. human renin than the comparable Sta-containing inhibitor 1 and 17 times more potent vs. dog renin than 1.Inhibitor 3 lowered blood pressure in sodium-deficient dogs, with in vivo potency 19 times that shown by 1, in close agreement with the relative in vitro potencies.Structure-activity results are presented that show the minimal N-terminus for these inhibitors.An ACHPA-containing pentapeptide, N--L-phenylalanyl-L-histydyl-ACHPA-L-lecyl-L-phenylalanyl amide , retained subnanomolar inhibitory potency.Molecular modelling studies are described that suggested the design of ACHPA.
- Boger, Joshua,Payne, Linda S.,Perlow, Debra S.,Lohr, Nancy S.,Poe, Martin,et al.
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p. 1779 - 1790
(2007/10/02)
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