60115-45-9Relevant academic research and scientific papers
Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor α release in vitro and in vivo
Xue,Voss,Nelson,Duan,Cherney,Jacobson,He,Roderick,Chen,Corbett,Wang,Meyer,Kennedy,Degrado,Hardman,Teleha,Jaffee,Liu,Copeland,Covington,Christ,Trzaskos,Newton,Magolda,Wexler,Decicco
, p. 2636 - 2660 (2007/10/03)
To search for TNF-α (tumor necrosis factor α) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2′ residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1 P1-P2′ linkers. With an N-methylamide at P3′, the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-α release from LPS-stimulated human whole blood. Further elaboration in the P3′-P4′ area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC50 values of ≤0.2 μM in whole blood assay (WBA). Although the P3′ area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3′ was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3′, an N-methylamide at P4′ provided the best cyclophane analogue, SL422 (WBA IC50 = 0.22 μM, LPS-mouse ED50 = 15 mg/kg, po), whereas a morpholinylamide at P4′ afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBAIC50 = 0.067 μM, LPS-mouse ED50 = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with Ki values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.
S-Aryl cysteine S,S-dioxides as inhibitors of mammalian kynureninase
Drysdale, Martin J.,Reinhard, John F.
, p. 133 - 138 (2007/10/03)
A series of 2-amino-S-aryl cysteine S,S-dioxides have been synthesised and shown to inhibit kynureninase an important enzyme in the biosynthesis of the known excitotoxic moiety quinolinic acid. The most potent of these, 2-amino-5-methyl-S-phenyl cysteine S,S-dioxide 6d, inhibits interferon-γ induced synthesis of quinolinic acid in human macrophages.
Detoxification Metabolism of o-Dinitrobenzene by the Yeast Issatchenkia orientalis
Tamaki, Hisanori,Kumagai, Hidehiko,Shimada, Yoshimi,Kashima, Takanori,Obata, Hiroshi,et al
, p. 951 - 956 (2007/10/02)
Culture medium containing 200 μM o-dinitrobenzene suppressed cell growth of Issatchenkia orientalis for about 24 hr and after a lag phase, the cells began to increase with concomitant metabolism of o-dinitrobenzene by glutathione conjugation.The resulting
Angiotensin converting enzyme inhibitors: 1,5-Benzothiazepine derivatives
Slade,Stanton,Ben-David,Mazzenga
, p. 1517 - 1521 (2007/10/02)
The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an ICsub
