- Design, synthesis, and structure-activity relationship studies of L-amino alcohol derivatives as broad-spectrum antifungal agents
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To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of L-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03–0.06 μg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1–2 μg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.
- Zhao, Liyu,Tian, Linfeng,Sun, Nannan,Sun, Yin,Chen, Yixuan,Wang, Xinran,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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p. 374 - 385
(2019/06/05)
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- Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
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Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.
- Cho, Young Shin,Levell, Julian R.,Liu, Gang,Caferro, Thomas,Sutton, James,Shafer, Cynthia M.,Costales, Abran,Manning, James R.,Zhao, Qian,Sendzik, Martin,Shultz, Michael,Chenail, Gregg,Dooley, Julia,Villalba, Brian,Farsidjani, Ali,Chen, Jinyun,Kulathila, Raviraj,Xie, Xiaoling,Dodd, Stephanie,Gould, Ty,Liang, Guiqing,Heimbach, Tycho,Slocum, Kelly,Firestone, Brant,Pu, Minying,Pagliarini, Raymond,Growney, Joseph D.
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supporting information
p. 1116 - 1121
(2017/10/18)
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- NOVEL PYRROLIDINE DERIVATIVES
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The invention relates to a compound of formula (I) wherein A and R1 to R7 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.
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Paragraph 0177
(2013/06/05)
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- Synthesis of proline analogues as potent and selective cathepsin S inhibitors
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Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor.
- Kim, Mira,Jeon, Jiyoung,Song, Jiyeon,Suh, Kwee Hyun,Kim, Young Hoon,Min, Kyung Hoon,Lee, Kwang-Ok
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p. 3140 - 3144
(2013/06/26)
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- NOVEL PYRROLIDINE DERIVATIVES AS INHIBITORS OF CATHEPSIN
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The invention relates to a compound of formula (I), wherein A and R1 to R7 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.
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Page/Page column 23
(2013/06/06)
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- Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines
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We report the synthesis and biological evaluation of a series of novel α-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12g has an IC50 of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 1 μg kg-1 at 1 h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride.
- Hunt, Thomas,Atherton-Watson, Hazel C.,Collingwood, Stephen P.,Coote, Kevin J.,Czarnecki, Sarah,Danahay, Henry,Howsham, Catherine,Hunt, Peter,Paisley, Derek,Young, Alice
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scheme or table
p. 2877 - 2879
(2012/05/20)
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- Synthesis of imidacloprid derivatives with a chiral alkylated imidazolidine ring and evaluation of their insecticidal activity and affinity to the nicotinic acetylcholine receptor
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A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5-position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified.
- Nishiwaki, Hisashi,Kuriyama, Mituhiro,Nagaoka, Hikaru,Kato, Akira,Yamauchi, Satoshi,Shuto, Yoshihiro,Akamatsu, Miki
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p. 6305 - 6312,8
(2012/12/11)
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- COMPOUNDS (CYSTEIN BASED LIPOPEPTIDES) AND COMPOSITIONS AS TLR2 AGONISTS USED FOR TREATING INFECTIONS, INFLAMMATIONS, RESPIRATORY DISEASES ETC.
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The invention provides a novel class of compounds viz. generally lipopeptides like Pam3CSK4, immunogenic compositions and pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like Receptors 2. In one aspect, the compounds are useful as adjuvants for enhancing the effectiveness a vaccine.
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Page/Page column 129
(2011/10/13)
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- COMPOUNDS AND COMPOSITIONS AS CATHEPSIN S INHIBITORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cathepsin S.
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Page/Page column 36
(2010/02/14)
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- HALOALKYL CONTAINING COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The application is directed to haloalkyl-substituted compounds of Formula (I), wherein R1, R1a, R2, R3, R4’ and E are as defined in the claims. The compounds are inhibitors of cysteine proteases, in p
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Page/Page column 52-53
(2010/02/11)
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- AMIDINO COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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Page/Page column 22
(2010/02/12)
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- SILINANE COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is also directed to pharmaceutical compositions comprising these compounds and processes for preparing them. The present invention is also directed to the use of these inhibitors in combination with a therapy that causes a deleterious immune response in patients receiving the therapy.
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Page/Page column 57-58
(2008/06/13)
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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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- Enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes: Synthesis and antitumor activity against MCF-7 and MDA-MB 231 breast cancer and LnCaP/FGC prostate cancer cell lines
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Enantiomerically pure 1,2-diamino-1-(4-fluorophenyl)butanes were synthesized by stereoselective procedures. The enantiomeric purity was determined by 1H NMR spectroscopy after derivatization with (1R)-myrtenal. For the coordination to platinum,
- Dullin, Anja,Dufrasne, Francois,Gelbcke, Michael,Gust, Ronald
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p. 654 - 667
(2007/10/03)
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- AMIDINO COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceu
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Page/Page column 50-51
(2010/02/09)
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- PEPTIDIC COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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- Short synthesis of protease inhibitors via modified Passerini condensation of N-Boc-α-aminoaldehydes
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Extension of the previously reported modification of Passerini multicomponent reaction (involving condensation with N-Boc-α-aminoaldehydes followed by a deprotection-transacylation step) to α-aminoacid derived carboxylic or isocyanide components, allowed the highly convergent and short synthesis of complex peptidomimetic structures, including known potent inhibitors of serine proteases.
- Banfi, Luca,Guanti, Giuseppe,Riva, Renata,Basso, Andrea,Calcagno, Emiliano
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p. 4067 - 4069
(2007/10/03)
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- Synthesis and biological evaluation of pyridine-modified analogues of 3-(2-aminoethoxy)pyridine as novel nicotinic receptor ligands
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Analogues of the potent nicotinic receptor agonist 3-(2-aminoethoxy)pyridine substituted at the 5′ and 6′-positions of the pyridine ring were synthesized and tested in vitro for nicotinic receptor binding activity (displacement of [3H](-)cytisine from whole rat brain synaptic membranes). The substituted analogues exhibited Ki values ranging from 0.076 to 319 nM compared to a Ki value of 26 nM for compound 1. Among the compounds tested, 5′-vinyl-6′-chloro substituted 1 was the most potent.
- Lin, Nan-Horng,Dong, Liming,Bunnelle, William H,Anderson, David J,Meyer, Michael D
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p. 3321 - 3324
(2007/10/03)
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- Isolation and structure determination of obyanamide, a novel cytotoxic cyclic depsipeptide from the marine cyanobacterium Lyngbya confervoides
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Obyanamide (1) was isolated from a variety of the marine cyanobacterium Lyngbya confervoides collected in Saipan, Commonwealth of the Northern Mariana Islands. Gross structure elucidation of this novel cyclic depsipeptide relied on extensive application of 2D NMR techniques. The absolute stereochemistry was deduced by chiral chromatography of the hydrolysis products and comparison with authentic and synthetic standards. Obyanamide (1) was cytotoxic against KB cells with an IC50 of 0.58 μg/mL.
- Williams, Philip G.,Yoshida, Wesley Y.,Moore, Richard E.,Paul, Valerie J.
-
-
- Asymmetric synthesis of β-amino alcohols and 1,2-diamines through DuPHOS-Rh catalysed hydrogenation
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A novel enantioselective synthesis of β-amino alcohols and 1,2-diamines is reported which incorporates the first description of the asymmetric hydrogenation of dehydro-β-amino alcohols and dehydro-α-amino aldoximes.
- Burk, Mark J.,Johnson, Nicholas B.,Lee, Jeffrey R.
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p. 6685 - 6688
(2007/10/03)
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- Asymmetric syntheses of (R)- and (S)-2-aminobutanesulfonic acid and their 3,3-dimethylderivatives
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(R)- and (S)-2-aminobutanesulfonic acid, 3a and 3b, and (R)- and (S)-2-amino-3,3-dimethylbutanesulfonic acid, 4a and 4b, were synthesized from the corresponding N-Boc protected β-amino alcohols in good yields and high enantiomeric purities (> 99% ee).
- Braghiroli, Daniela,Di Bella, Maria
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p. 2145 - 2150
(2007/10/03)
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- Synthesis of enantiopure N-and C-protected homo-β-amino acids by direct homologation of α-amino acids
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Enantiopure N-and/or C-protected homo-β-amino acids are prepared readily and in good yields from N-protected α-amino acids with the same side chain, via reduction of the carboxyl function and conversion of the resulting N-protected β-amino alcohol into the corresponding β-amino iodide and then β-amino cyanide. The key step of this strategy is represented by the synthesis of the enantiopure N-protected β-amino iodides 2 and 3 that are smoothly obtained from the parent amino alcohols 1 by polymer bound triarylphosphine-I2 complex in anhydrous dichloromethane.
- Caputo, Romualdo,Cassano, Ersilia,Longobardo, Luigi,Palumbo, Giovanni
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p. 12337 - 12350
(2007/10/02)
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- Chiral N-Protected β-Iodoamines from α-Aminoacids: a General Synthesis
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N-Protected D- or L-β-iodoamines (as 2), which are useful intermediates for the preparation of chiral β-aminoacids, are obtained smoothly from β-aminols (as 1) in two steps and high yields.
- Caputo, Romualdo,Cassano, Ersilia,Longobardo, Luigi,Palumbo, Giovanni
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p. 167 - 168
(2007/10/02)
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