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N-Methyl-D-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC50 values in a Ca2+ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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The syntheses and characterisation of a series of chiral and achiral 2-(aminophenyl)-2-oxazolines and some related compounds is reported. All of the derivatives have been produced by a one-step procedure involving the treatment of isatoic anhydride (i.e. [2H]-3,1-benzoxazine-[1H]-2,4-dione: 1) or its 5-chloro analogue with a slight excess of appropriate amino-alcohols. In most cases, anhydrous ZnCl2 is shown to be an effective Lewis acid catalyst for this reaction at reflux temperature in high boiling aromatic solvents (PhCl or PhMe). Oxazolines have been readily formed using rac-2-amino-1-butanol, (S)-phenylglycinol, 2-methyl-2-amino-1-propanol and (1S, 2R) or (1R, 2S)-cis-1-amino-2-indanol; yields range from 85% to 22%. The use of aminoalcohols such as 2-ethanolamine, (±)-2-amino-1-phenyl-1-propanol or 3-amino-1-propanol (to give the corresponding 4,5-dihydro-1,3-oxazine) results in poor yields. The use of other Lewis acid catalysts (silicic acid, Cd(acac)2?2H2O, CuCl2?2H2O, InCl3) or higher temperatures did not improve the yields with these latter two substrates. Benzoxazoles and N-substituted benzoxazoles can also be obtained in reasonable yields from 1 using 2-aminophenol (36%) or 2-amino-3-hydroxypyridine (45%).

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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The first enantioselective alpha-hydroxylation reaction of alpha-substituted -ketoamides has been developed by using the commercially available hydroquinine/TBHP system. The tertiary alcohols are obtained in good to high yield and up to 83% ee, which can be improved by a single crystallization.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 Ki = 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa Ki of 0.50 nM, PT EC2x of 2.1 muM in human plasma, bioavailability of 25% and t1/2of 2.7 h in dogs. Further biochemical characterization of compound 31 is also presented.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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A new class of oxazaborolidine catalysts has been prepared from optically pure cis-1-amino-2 indanols which are available in large quantities. The asymmetric borane reduction of aromatic ketones using these catalysts has been studied.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Benzoxazole and benzothiazole compounds and the stereoisomers, tautomers, solvates, oxides, esters, and prodrugs thereof and pharmaceutically acceptable salts thereof are disclosed. Compositions of the compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier, and uses of the compounds, either alone or in combination with at least one additional therapeutic agent are also disclosed. The embodiments are useful for inhibiting cellular proliferation, inhibiting the growth and/or metathesis of tumors, treating or preventing cancer, treating or preventing degenerating bone diseases such as rheumatoid arthritis, and/or inhibiting molecules such as CSF-1R.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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A 1X22X41 combinatorial library or 902 compounds of indinavir analogues was synthesized on the solid support to identify a replacement for the aminoindanol moiety at P2?. 2,6-Dimethyl-4-hydroxy phenol was discovered to be a good replacement for aminoindanol.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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A simple procedure is presented for preparing 1,3-thiazolidine-2-thiones by using potassium ethylxanthate and the corresponding beta -amino alcohols as the starting materials in the presence of ethanol.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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It was found that the tridentate O,N,O-type Schiff base ligand bearing suitable substituents was a highly effective promoter in the catalytic asymmetric bromochlorination reaction, in which the corresponding aromatic bromochloroalcohols with vicinal halogen-bearing stereocenters were formed with perfect regioselectivity, with moderate to excellent enantioselectivities (up to 93% ee), and with good yields and chemoselectivities.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis