- Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors
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8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket.
- Nowak, Pawel,Cole, Derek C.,Aulabaugh, Ann,Bard, Jonathan,Chopra, Rajiv,Cowling, Rebecca,Fan, Kristi Y.,Hu, Baihua,Jacobsen, Steve,Jani, Minakshi,Jin, Guixan,Lo, Mei-Chu,Malamas, Michael S.,Manas, Eric S.,Narasimhan, Rani,Reinhart, Peter,Robichaud, Albert J.,Stock, Joseph R.,Subrath, Joan,Svenson, Kristine,Turner, Jim,Wagner, Erik,Zhou, Ping,Ellingboe, John W.
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scheme or table
p. 632 - 635
(2010/06/12)
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- Design, synthesis, and preliminary evaluation of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives as potential iNOS inhibitors
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A series of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives were synthesized and evaluated for their abilities to inhibit inducible nitric oxide synthase (iNOS) isoform. All target compounds were prepared in 11 steps from commercially trans-4-hydroxy-l-proline. The preliminary pharmacological test showed that three compounds, 17, 21, and 30, have the good potency (IC50 = 2.36, 2.68, 2.5 μM, respectively) which are compared to the NOS inhibitor NG-nitroarginine(L-NNA) (IC50 = 14.74 μM), and could be used as lead compounds for exploring new iNOS inhibitors in the future.
- Liu, Feng-Zhi,Fang, Hao,Zhu, Hua-Wei,Wang, Qiang,Yang, Yue,Xu, Wen-Fang
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p. 578 - 585
(2008/04/12)
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- Mass labels
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Provided is a set of two or more mass labels, each label in the set comprising a mass marker moiety attached via a cleavable linker having at least one amide bond to a mass normalisation moiety, wherein the aggregate mass of each label in the set may be the same or different and the mass of the mass marker moiety of each label in the set may be the same or different, and wherein in any group of labels within the set having a mass marker moiety of a common mass each label has an aggregate mass different from all other labels in that group, and wherein in any group of labels within the set having a common aggregate mass each label has a mass marker moiety having a mass different from that of all other mass marker moieties in that group, such that all of the mass labels in the set are distinguishable from each other by mass spectromety, and wherein the mass marker moiety comprises an amino acid and the mass normalisation moiety comprises an amino acid.
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- Tandem mass tags: A novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS
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A novel MS/MS-based analysis strategy using isotopomer labels, referred to as "tandem mass tags" (TMTs), for the accurate quantification of peptides and proteins is described. The new tags are designed to ensure that identical peptides labeled with different TMTs exactly comigrate in all separations. The tags require novel methods of quantification analysis using tandem mass spectrometry. The new tags and analysis methods allow peptides from different samples to be identified by their relative abundance with greater ease and accuracy than other methods. The new TMTs permit simultaneous determination of both the identity and relative abundances of peptide pairs using a collision induced dissociation (CID)-based analysis method. Relative abundance measurements made in the MS/MS mode using the new tags are accurate and sensitive. Compared to MS-mode measurements, a very high signal-to-noise ratio is achieved with MS/MS based detection. The new tags should be applicable to a wide variety of peptide isolation methods.
- Thompson, Andrew,Schaefer, Juergen,Kuhn, Karsten,Kienle, Stefan,Schwarz, Josef,Schmidt, Guenter,Neumann, Thomas,Hamon, Christian
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p. 1895 - 1904
(2007/10/03)
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- Wrinkle-care product
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A wrinkle-care product, an aging-preventive cosmetic and a skin cosmetic each comprising a guanidine derivative of formula (I) or an acid addition salt thereof: STR1 wherein R1 represents a hydrogen atom, a lower alkyl group or --(AO)m --(BO)n --D--E ?wherein A and B may be the same or different and each represents an alkylene group having 2 to 8 carbon atoms; D represents a binding hand, --CO--, or an unsubstituted or substituted alkylene group having 1 to 6 carbon atoms; E represents a hydrogen atom, a lower alkyl group, an aralkyl group or an unsubstituted or substituted aryl group; m is a number of from 1 to 6; and n is a number of from 0 to 6!; k is a number of from 1 to 10; and G represents a hydrogen atom, a hydroxyl group, a carboxyl group, a sulfonate group or a phosphate group. These products are excellent in the effects of inhibiting wrinkling and smoothing wrinkles without damaging the physiological conditions of the skin.
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- Methods and compositions for inducing resistance to bacterial infections
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A variety of substances are reported which alter host resistance to cocci and bacilli bacterial infections. Nevertheless, because of the extreme difficulty of total eradication, and the frequent reappearance of the same strains, even after their apparently successful elimination, there is a continuing need for drugs for the treatment of coccic infections. Certain guanidinoacylhistidines are effective in inducing resistance to infections due to cocci and bacilli.
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