74292-74-3Relevant academic research and scientific papers
4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
Zhi, Ying,Gao, Li-Xin,Jin, Yi,Tang, Chun-Lan,Li, Jing-Ya,Li, Jia,Long, Ya-Qiu
, p. 3670 - 3683 (2014/07/07)
Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC 50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups
Fan, Xing,Zhang, Feng-Hua,Al-Safi, Rasha I.,Zeng, Li-Fan,Shabaik, Yumna,Debnath, Bikash,Sanchez, Tino W.,Odde, Srinivas,Neamati, Nouri,Long, Ya-Qiu
experimental part, p. 4935 - 4952 (2011/09/30)
HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC50 = 5 μM) with more than 40-fold selectivity for the strand transfer over the 3′-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3- dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC50 value of 8 μM. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors.
DIBENZOXAZEPINE
-
Page/Page column 44-45, (2010/02/06)
The invention relates to compounds, a method for the production thereof, pharmaceutical compositions containing said compounds and to the utilization thereof in the treatment and/or prophylaxis of diseases in human beings or animals, especially cardiovascular diseases, for example, arteriosclerosis.
Synthesis and absolute configuration of (-)-3-butyl-7-hydroxyphthalide, a cytotoxic metabolite of Penicillium vulpinum.
Ohzeki, Tomoya,Mori, Kenji
, p. 2240 - 2244 (2007/10/03)
Both the enantiomers as well as the racemate of 3-butyl-7-hydroxyphthalide (1) were synthesized, and the absolute configuration of the naturally occurring (-)-1 (a weakly cytotoxic metabolite of Penicillium vulpinum) was identified as S.
IL-8 receptor antagonists
-
, (2008/06/13)
This invention relates to novel compounds of Formula (1), pharmaceutical compositions and their use in the treatment of disease states mediated by the chemokine, Interleukins-8 (IL-8).
2-(Alkylamino)nicotinic Acid and Analogs. Potent Angiotensin II Antagonists
Winn, Martin,De, Biswanath,Zydowsky, Thomas M.,Altenbach, Robert J.,Basha, Fatima Z.,et al.
, p. 2676 - 2688 (2007/10/02)
A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a-CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists.In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring.The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin II antagonism.The pyridine (W, X, Y = CH, Z = COOH, R' = n-C3H7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability.Any nonacidic replacement for the carboxylic acid was detrimental for activity.
SELECTIVE MONO O-ALKYLATION OF γ-RESORCYLYC ESTERS
Bass, R. J.,Banks, B. J.,Snarey, M.
, p. 769 - 770 (2007/10/02)
The use of diethylazodicarboxylate/triphenylphosphine for the selective mono-O-alkylation of γ-resorcylic esters is described.
