89525-07-5Relevant academic research and scientific papers
Practical spectrophotometric assay for the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase, a potential antibiotic target
Heath, Tahirah K.,Lutz, Marlon R.,Reidl, Cory T.,Guzman, Estefany R.,Herbert, Claire A.,Nocek, Boguslaw P.,Holz, Richard C.,Olsen, Kenneth W.,Ballicora, Miguel A.,Becker, Daniel P.
, (2018)
A new enzymatic assay for the bacterial enzyme succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) is described. This assay employs N6-methyl-N2-succinyl-L,L-diaminopimelic acid (N6-methyl-L,L-SDAP) as the substrate with ninhydrin used to detect cleavage of the amide bond of the modified substrate, wherein N6-methylation enables selective detection of the primary amine enzymatic product. Molecular modeling supported preparation of the mono-N6-methylated-L,L-SDAP as an alternate substrate for the assay, given binding in the active site of DapE predicted to be comparable to the endogenous substrate. The alternate substrate for the assay, N6-methyl-L,L-SDAP, was synthesized from the tert-butyl ester of Boc-L-glutamic acid employing a Horner-Wadsworth-Emmons olefination followed by an enantioselective reduction employing Rh(I)(COD)(S,S)-Et-DuPHOS as the chiral catalyst. Validation of the new ninhydrin assay was demonstrated with known inhibitors of DapE from Haemophilus influenza (HiDapE) including captopril (IC50 = 3.4 [± 0.2] μM, 3-mercaptobenzoic acid (IC50 = 21.8 [±2.2] μM, phenylboronic acid (IC50 = 316 [± 23.6] μM, and 2-thiopheneboronic acid (IC50 = 111 [± 16] μM. Based on these data, this assay is simple and robust, and should be amenable to high-throughput screening, which is an important step forward as it opens the door to medicinal chemistry efforts toward the discovery of DapE inhibitors that can function as a new class of antibiotics.
MACROCYCLIC INHIBITORS OF THE PD-1/PD-L1 AND CD80/PD-L1 PROTEIN/PROTEIN INTERACTIONS
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Page/Page column 143, (2017/11/04)
The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-Ll and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases. wherein: A is selected from a bond.
4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y12 Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel
Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
, p. 9133 - 9153 (2015/12/23)
Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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Page/Page column 268, (2009/01/20)
The embodiments provide compounds of the general Formula I, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
Total synthesis of azinomycin A
Coleman, Robert S.,Li, Jing,Navarro, Antonio
, p. 1736 - 1739 (2007/10/03)
A most elusive of synthesis targets, azinomycin A 1 has now been synthesized for the first time. Using a modular synthetic approach, and after considerable developmental effort, this antitumor agent has been synthesized in a stereocontrolled manner using
Efficient stereoselective preparation of protected isodityrosines
Jorgensen, Kare.B.,Gautun, Odd.R.
, p. 10527 - 10536 (2007/10/03)
A method for stereoselective preparation of isodityrosines with identical and orthogonal protecting groups is reported. The isodityrosines holding identical protecting groups were prepared from isovaniline in a three step procedure, in 50-64% yield (> 98% ee, 84-96% de). Isodityrosine holding four orthogonal groups was prepared in four steps from isovaniline in 20% total yield (> 98% ee, 87% de).
An efficient synthesis of (pyrrolidin-2-ylidene)glycinate using intramolecular 1, 3-dipolar cycloaddition of azide and olefin
Konda, Yaeko,Sato, Takahiro,Tsushima, Kaori,Dodo, Masataka,Kusunoki, Ami,Sakayanagi, Masataka,Sato, Noriko,Takeda, Kazuyoshi,Harigaya, Yoshihiro
, p. 12723 - 12740 (2007/10/03)
Methyl and tert-butyl (E-)-(pyrrolidin-2-ylidene)glycinates 3a and 3b were efficiently and stereoselectively synthesized from 2, 3, 5-tri-O- benzylarabinose using Horner-Emmons olefination of arabinal 9 and phosphorylglycine ester and intramolecular 1, 3-
Phosphono analogues of glutathione as new inhibitors of glutathione S-transferases
Kunze, Thomas
, p. 503 - 509 (2007/10/03)
Phosphono-analogues of glutathione containing the O=P(OR)2 moiety in place of the cysteinyl residue CH2SH 1a-1d were prepared by solution phase peptide synthesis. Benzyl, benzyloxycarbonyl, and tert-butyl protecting groups were used
Synthesis of enantiomerically pure D- and L-(heteroaryl)alanines by asymmetric hydrogenation of (Z)-α-amino-α,β-didehydro esters
Masquelin,Broger,Muller,Schmid,Obrecht
, p. 1395 - 1411 (2007/10/02)
Homogeneous asymmetric hydrogenation of a wide range of methyl and tert-butyl (Z)-2-(acylamino)-3-(heteroaryl)acrylates (see 1a-f and 2a-d, f, g, resp.) catalyzed by diphosphinerhodium catalysts was studied for the synthesis of enantiomerically pure 3-fur
Synthesis of acyclic and dehydroaspartic acid analogues of Ac-Asp-Glu-OH and their inhibition of rat brain N-acetylated α-linked acidic dipeptidase (NAALA dipeptidase)
Subasinghe,Schulte,Chan,Roon,Koerner,Johnson
, p. 2734 - 2744 (2007/10/02)
The following structural and conformationally constrained analogues of Ac-Asp-Glu-OH (1) were synthesized: Ac-Glu-Glu-OH (2), Ac-D-Asp-Glu-OH (3), Ac-Glu-Asp-OH (4), Ac-Asp-Asp-OH (5), Ac-Asp-3-aminohexanedioic acid (6), Ac-3-amino-3-(carboxymethyl)propanoyl-Glu-OH (7), N-succinyl-Glu-OH (8), N-maleyl-Glu-OH (9), N-fumaryl-Glu-OH (10), and Ac-Δ(z)Asp-Glu-OH (11). These analogues were evaluated for their ability to inhibit the hydrolysis of Ac-Asp-[3,4-3H]-Glu-OH by N-acetylated α-linked acidic dipeptidase (NAALA dipeptidase) in order to gain some insight into the structural requirements for the inhibition of this enzyme. Analogues 4-6 and 9 were very weak inhibitors of NAALA dipeptidase (K(i) > 40 μM), while 2, 3, and 7 with K(i) values ranging from 3.2-8.5 μM showed intermediate inhibitory activity. The most active inhibitors of NAALA dipeptidase were compounds 8, 10, and 11 with K(i) values of 0.9, 0.4, and 1.4 μM, respectively. These results suggest that the relative spacing between the side chain carboxyl and the α-carboxyl group of the C-terminal residue may be important for binding to the active site of the enzyme. They also indicate that the χ1 torsional angle for the aspartyl residue is in the vicinity of 0°.
