- Design, synthesis and evaluation of novel 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as potent, selective and reversible Bruton's tyrosine kinase (BTK) inhibitors for the treatment of rheumatoid arthritis
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A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized as reversible BTK inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line BTK enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC50 = 3.0 nM against BTK enzyme, 8.52 μM, 11.10 μM and 7.04 μM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited BTK Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change.
- Zhang, Chufeng,Pei, Heying,He, Jun,Zhu, Jiali,Li, Weimin,Niu, Ting,Xiang, Mingli,Chen, Lijuan
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p. 121 - 143
(2019/03/13)
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- Design, synthesis, and antileukemic activity of stereochemically defined constrained analogues of FTY720 (Gilenya)
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FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has antineoplastic actions. Our published work suggests that at least some of FTY720's anticancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective antitumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for antileukemic activity.
- Fransson, Rebecca,McCracken, Alison N.,Chen, Bin,McMonigle, Ryan J.,Edinger, Aimee L.,Hanessian, Stephen
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p. 969 - 973
(2013/10/22)
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- TRANS-3,5-DISUBSTITUTEDPYRROLIDINE: ORGANOCATALYST FOR anti-MANNICH REACTIONS
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A compound of Formula I is disclosed, in which R is a substituent containing a hydrogen bond-forming atom within three atoms from the ring carbon to which the substituent is bonded; X is CH2, O, S or NR1, wherein R1 is a hydrocarbyl group or an amino-protecting group having one to about 18 carbon atoms; R2 is hydrido or a hydrocarbyl group containing one to about twelve carbon atoms; and R3 is hydrido or methyl, but both R2 and R3 are not hydrido when X is CH2 A molecule of Formula I and those in which R2 and R3 can both be hydrido (Formula X) functions as a catalyst in a Mannich reaction to asymmetrically form β-aminoaldehyde or β-aminoketone diastereomeric products having two chiral centers on adjacent carbon atoms and in which the anti-diastereomers are in excess over the syn-diastereomers. Methods for carrying out those syntheses are also disclosed.
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Page/Page column 21; 22
(2010/11/27)
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- Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid
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The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1-5 mol %) is reported. Based on principles gained from the study of (S)-
- Mitsumori, Susumu,Zhang, Haile,Cheong, Paul Ha-Yeon,Houk,Tanaka, Fujie,Barbas, Carlos F.
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p. 1040 - 1041
(2007/10/03)
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- Regioselective directed lithiation of N-Boc 3-hydroxypyrrolidine. Synthesis of 2-substituted 4-hydroxypyrrolidines
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N-Boc 3-hydroxypyrrolidine 1 undergoes directed C-lithiation at C5 and not, as previously reported, at C2; the resulting dilithiated intermediate 6 has been trapped by a range of electrophiles to give 2-substituted 4-hydroxypyrrolidines 7.
- Sunose, Mihiro,Peakman, Torren M.,Charmant, Jonathan P. H.,Gallagher, Timothy,Macdonald, Simon J. F.
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p. 1723 - 1724
(2007/10/03)
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- 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds
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1-Azabicyclo[3.2.0]hept-2-ene-2-carboxyic acids having antimicrobial activity have been prepared.
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- Design, Synthesis, and Properties of (4S)-7-(4-Amino-2-substituted-pyrrolidin-1-yl)quinolone-3-carboxylic Acids
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The quinolinecarboxylic acids constitute a class of extremely potent and orally active broad-spectrum antibacterial agents.These compounds have been shown to inhibit DNA gyrase, a key enzyme in bacterial DNA replication.The 7-(3-aminopyrrolidinyl)quinolone A-60969 (1) is a particularly potent member of this class and is currently undergoing clinical evaluation.We have studied a series of enantiomerically homogeneous (4S)-7-(4-amino-2-substituted-pyrrolidinyl)quinolones in an effort to utilize the 2-position of the pyrrolidine moiety to improve upon the solubility and pharmacokinetic properties of this class of compounds while still maintaining potent antibacterial activity.We have found that the absolute stereochemistry at the 2-position of the pyrrolydine ring is critical to the maintenance of such activity.In this paper, we report the full details of the asymmetric synthesis and the in vitro and in vivo structure-activity relationships of this series of compounds as well as the physiochemical properties, such as water solubility and log P, associated with the structural modifications.We also discuss the pharmacokinetic properties of several of these compounds in mice and the pharmacokinetics of 59, which has the best overall properties of agents in this study, in dog.
- Rosen, Terry,Chu, Daniel T. W.,Lico, Isabella M.,Fernandes, Prabhavathi B.,Marsh, Kennan,et al.
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p. 1598 - 1611
(2007/10/02)
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