- TRIAZOLE DERIVATIVES AS P2Y14 RECEPTOR ANTAGONISTS
-
Described are compounds, which are antagonists of the P2Y14 receptor, for example, a compound of formula (I) in which ring A, R1,R2, R3, and n are as described herein. Also provided are dendron conjugates comprising the compounds, and methods of using the compounds, including a method of treating a disorder, such as inflammation, diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, a condition associated with metabolic syndrome, and asthma, and a method of antagonizing P214 receptor activity in a cell.
- -
-
Paragraph 0115; 0116
(2017/04/11)
-
- PYRROLO[3,2-C]PYRIDINE DERIVATIVES AS TLR INHIBITORS
-
The present invention provides a heterocyclic compound having a TLR7, TLR9, TLR7/8, TLR7/9 or TLR7/8/9 inhibitory action, which is useful as an agent for the prophylaxis or treatment of autoimmune diseases, inflammatory diseases and the like, in particular, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease and the like. The present invention is a compound represented by the formula (1): wherein each symbol is as described in the specification, or a salt thereof.
- -
-
-
- Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists
-
UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models.
- Junker, Anna,Balasubramanian, Ramachandran,Ciancetta, Antonella,Uliassi, Elisa,Kiselev, Evgeny,Martiriggiano, Chiara,Trujillo, Kevin,Mtchedlidze, Giorgi,Birdwell, Leah,Brown, Kyle A.,Harden, T. Kendall,Jacobson, Kenneth A.
-
supporting information
p. 6149 - 6168
(2016/07/26)
-
- METALLO-BETA-LACTAMASE INHIBITORS
-
The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
- -
-
-
- METALLO-BETA-LACTAMASE INHIBITORS
-
The present invention relates to compounds of formula I that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
- -
-
-
- PYRROLO[3,2-C]PYRIDINE DERIVATIVES AS TLR INHIBITORS
-
The present invention provides a heterocyclic compound having a TLR7, TLR9, TLR7/8, TLR7/9 or TLR7/8/9 inhibitory action, which is useful as an agent for the prophylaxis or treatment of autoimmune diseases, inflammatory diseases and the like, in particular, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease and the like. The present invention is a compound represented by the formula (1): wherein each symbol is as described in the specification, or a salt thereof.
- -
-
-
- METALLO-BETA-LACTAMASE INHIBITORS
-
The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
- -
-
-
- 4 ( 1H) -PYRIDINONE DERIVATIVES AND THEIR USE AS ANTIMALARIA AGENTS
-
4-pyridone (4-pyridinone) derivatives of Formula (I) and pharmaceutically acceptable derivatives thereof, processes for their preparation, pharmaceutical formulations thereof and their use in chemotherapy of certain parasitic infections such as malaria, are provided.
- -
-
Page/Page column 38
(2010/08/08)
-
- INHIBITORS OF THE BMP SIGNALING PATHWAY
-
The present invention provides small molecule inhibitors of BMP signaling. These compounds may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation.
- -
-
Page/Page column 83
(2009/10/22)
-
- HETEROCYCLIC COMPOUNDS AND USE THEREOF AS ERK INHIBITORS
-
Disclosed are the ERK inhibitors of formula 1.0: [Formula (1.0)] and the pharmaceutically acceptable salts, esters and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
- -
-
Page/Page column 199
(2009/01/23)
-
- A novel class of nonpeptidic biaryl inhibitors of human cathepsin K
-
A novel series of nonpeptidic biaryl compounds was identified as potent and reversible inhibitors of cathepsin K. The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins. Structural modification within this series resulted in the identification of compound (R)-2, a potent human cathepsin K inhibitor (IC50 = 3 nM) that is selective versus cathepsins B (IC50 = 3950 nM), L (IC50 = 3725 nM), and S (IC50 = 2010 nM). In an in vitro assay involving rabbit osteoclasts and bovine bone, compound (R)-2 inhibited bone resorption with an IC 50 of 95 nM. It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K. This indicates that this class of nonpeptidic nitrile inhibitors is unlikely to be hydrolyzed by cysteine proteases. Furthermore, the inhibition of cathepsin K by compound (R)-2 was shown to be fully reversible and not observably time-dependent. To demonstrate the efficacy of compound (R)-2 in vivo, it was administered to ovariectomized (OVX) rhesus monkeys at 20 mg/kg, po once daily for 8 days, and a urinary marker of bone turnover, N-telopeptide of type I collagen (uNTx), was measured. During the eight-day dosing period, the mean reduction by compound (R)-2 in uNTx was 80% (p 0.001). This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis.
- Robichaud, Jo?l,Oballa, Renata,Prasit, Peppi,Falgueyret, Jean-Pierre,Percival, M. David,Wesolowski, Gregg,Rodan, Sevgi B.,Kimmel, Donald,Johnson, Colena,Bryant, Cliff,Venkatraman, Shankar,Setti, Eduardo,Mendonca, Rohan,Palmer, James T.
-
p. 3709 - 3727
(2007/10/03)
-
- Design and synthesis of orally active inhibitors of TNF synthesis as anti-rheumatoid arthritis drugs
-
A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic
- Chen, Jian Jeffrey,Dewdney, Nolan,Lin, Xiaohong,Martin, Robert L.,Walker, Keith A. M.,Huang, Jane,Chu, Frances,Eugui, Elsie,Mirkovich, Anna,Kim, Yong,Sarma, Keshab,Arzeno, Humberto,Van Wart, Harold E.
-
p. 3951 - 3954
(2007/10/03)
-
- Piperidine derivatives having renin inhibiting activity
-
Novel piperidine derivatives, their manufacture and use as medicaments, are disclosed. The invention is concerned with the novel piperidine derivatives of general formula I wherein R1, R2, R3, R4, Q, X, Z, m and n are as described herein.
- -
-
-