Nonsteroidal antiinflammatory agents. 1. 5-Alkoxy-3-biphenylylacetic acids and related compounds as new potential antiinflammatory agents

Tamura, Yasumitsu; Yoshimoto, Yoshihiko; Kunimoto, Katsutoshi; Tada, Satoru; Tomita, Toshio; Wada, Toshiyuki; Seto, Eisuke; Murayama, Masao; Shibata, Yoshihisa

doi:10.1021/jm00215a018

Cited by 19 publications

(12 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7 This two-step procedure made it possible to apply parallel synthesis methods. Commercially available or previously synthesized aldehydes ( 1 ) were used as starting materials, which were conveniently converted to intermediates 2 in high yields.…”

Section: Resultsmentioning

confidence: 99%

Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells

Zhang

Benmohamed²,

Arvanites³

et al. 2012

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Currently, there is only one FDA-approved treatment for ALS (riluzole), and that drug only extends life, on average, by 2–3 months. Mutations in Cu/Zn superoxide dismutase (SOD1) are found in familial forms of the disease and have played an important role in the study of ALS pathophysiology. On the basis of their activity in a PC12-G93A-YFP high-throughput screening assay, several bioactive compounds have been identified and classified as cyclohexane-1,3-dione (CHD) derivatives. A concise and efficient synthetic route has been developed to provide diverse CHD analogs. The structural modification of the CHD scaffold led to the discovery of a more potent analog (26) with an EC50 of 700 nM having good pharmacokinetic properties, such as high solubility, low human and mouse metabolic potential, and relatively good plasma stability. It was also found to efficiently penetrate the blood-brain barrier. However, compound 26 did not exhibit any significant life span extension in the ALS mouse model. It was found that, although 26 was active in PC12 cells, it had poor activity in other cell types, including primary cortical neurons, indicating that it can penetrate into the brain, but is not active in neuronal cells, potentially due to poor selective cell penetration. Further structural modification of the CHD scaffold was aimed at improving global cell activity as well as maintaining potency. Two new analogs (71 and 73) were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency to that of 26 in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic candidates for ALS.

show abstract

Section: Resultsmentioning

confidence: 99%

Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells

Zhang

Benmohamed²,

Arvanites³

et al. 2012

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…Among the halogen-substituted compounds (2 -11), only compounds having the F or CF 3 group in the R position and the Cl or NH 2 group in the W position showed signifi-2-Amino-5-sulfanyl-1,3,4-thiadiazoles 23 (2,3,5,8,9,11). One possible reason could be that the fluorine atom is small in size, lipophilic in nature, has the ability to form strong H-bond, and has better metabolic stability under physiological condition.…”

Section: Resultsmentioning

confidence: 99%

2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a novel series of anti-inflammatory and analgesic agents

et al. 2009

View full text Add to dashboard Cite

2-Amino-5-sulfanyl-1,3,4-thiadiazole derivatives were synthesized via the interaction of 2-amino-5-sulfanyl-1,3,4-thiadiazole, Ar-Cl, and benzene sulfonamide/benzene sulfonyl chloride. Twelve compounds were synthesized, out of which six compounds show significant anti-inflammatory and analgesic activity and were devoid of gastrointestinal side effects (ulcerogenic effect), which zre the most frequent adverse reactions associated with orally ingested anti-inflammatory or antiarthritic agents.

show abstract

“…The strategy was to introduce a fluorine atom by replacement of the two methyl groups at position 4 in the Dde structure with a pF-phenyl ring. First, compound 1 [15] was reacted with acetyl chloride giving the enol ester 2. Subsequent isomerization in the presence of DMAP [16] produced compound 3 in 86% yield (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and application of N‐[1‐(4‐(4‐fluorophenyl)‐2,6‐dioxocyclohexylidene)ethyl] (Fde)‐protected amino acids for optimization of solid‐phase peptide synthesis using gel‐phase ¹⁹F NMR spectroscopy

Pudelko

Qian

Elofsson

2009

Journal of Peptide Science

View full text Add to dashboard Cite

N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde) protected amino acids have been prepared and applied in solid-phase peptide synthesis monitored by gel-phase (19)F NMR spectroscopy. The Fde protective group could be cleaved with 2% hydrazine or 5% hydroxylamine solution in DMF as determined with gel-phase (19)F NMR spectroscopy. The dipeptide Ac-L-Val-L-Val-NH(2) 12 was constructed using Fde-L-Val-OH and no noticeable racemization took place during the amino acid coupling with N,N'-diisopropylcarbodiimide and 1-hydroxy-7-azabenzotriazole or Fde deblocking. To extend the scope of Fde protection, the hydrophobic nonapeptide LLLLTVLTV from the signal sequence of mucin MUC1 was successfully prepared using Fde-L-Leu-OH at diagnostic positions.

show abstract

Nonsteroidal antiinflammatory agents. 1. 5-Alkoxy-3-biphenylylacetic acids and related compounds as new potential antiinflammatory agents

Cited by 19 publications

References 11 publications

Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells

Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells

2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a novel series of anti-inflammatory and analgesic agents

Synthesis and application of N‐[1‐(4‐(4‐fluorophenyl)‐2,6‐dioxocyclohexylidene)ethyl] (Fde)‐protected amino acids for optimization of solid‐phase peptide synthesis using gel‐phase ¹⁹F NMR spectroscopy

Contact Info

Product

Resources

About

Nonsteroidal antiinflammatory agents. 1. 5-Alkoxy-3-biphenylylacetic acids and related compounds as new potential antiinflammatory agents

Cited by 19 publications

References 11 publications

Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells

Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells

2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a novel series of anti-inflammatory and analgesic agents

Synthesis and application of N‐[1‐(4‐(4‐fluorophenyl)‐2,6‐dioxocyclohexylidene)ethyl] (Fde)‐protected amino acids for optimization of solid‐phase peptide synthesis using gel‐phase 19F NMR spectroscopy

Contact Info

Product

Resources

About

Synthesis and application of N‐[1‐(4‐(4‐fluorophenyl)‐2,6‐dioxocyclohexylidene)ethyl] (Fde)‐protected amino acids for optimization of solid‐phase peptide synthesis using gel‐phase ¹⁹F NMR spectroscopy