Synthesis and Selective Cyclooxygenase-2 Inhibitory Activity of a Series of Novel, Nitric Oxide Donor-Containing Pyrazoles

Ranatunge, Ramani R.; Augustyniak, Michael E.; Bandarage, Upul K.; Earl, Richard A.; Ellis, James L.; Garvey, David S.; Janero, David R.; Letts, L. Gordon; Martino, Allison M.; Murty, Madhavi G.; Richardson, Stewart K.; Schroeder, Jeremy W.; Shumway, Matthew J.; Tam, S. William; Trocha, A Mark; Young, Delano V.

doi:10.1021/jm030276s

Cited by 77 publications

(27 citation statements)

References 43 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Methylation of 2 with trimethylorthoformate in the presence of p-toluene sulfonic acid gave 3 in a 44% isolated yield (500 g). Reaction of 3 with known hydrazine, (tetrahydro-pyran-4-yl)-hydrazine (4) (Ranatunge et al, 2004), as the dihydrochloride in the presence of triethyl amine in methanol gave 5-amino-3-benzyloxymethyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carbonitrile (5) in a 80% crude yield (190 g). Reaction of 5 with formamide at elevated temperature effected a second ring closure to give the pyrazolpyrimidine (6) in a 73% (crude) yield (110 g).…”

Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Casein Kinase 1ϵ Minimally Alters Circadian Clock Period

Walton

Fisher²,

Rubitski³

et al. 2009

J Pharmacol Exp Ther

155

179

View full text Add to dashboard Cite

The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder, and metabolic disorders. Casein kinase 1 epsilon (CK1) and casein kinase 1 delta (CK1␦) are closely related Ser-Thr protein kinases that serve as key clock regulators as demonstrated by mammalian mutations in each that dramatically alter the circadian period. Therefore, inhibitors of CK1␦/ may have utility in treating circadian disorders. Although we previously demonstrated that a pan-CK1␦/ inhibitor, 4-[3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamine (PF-670462), causes a significant phase delay in animal models of circadian rhythm, it remains unclear whether one of the kinases has a predominant role in regulating the circadian clock. To test this, we have characterized 3-(3-, a novel and potent inhibitor of CK1 (IC 50 ϭ 32 nM) with greater than 20-fold selectivity over CK1␦. PF-4800567 completely blocks CK1-mediated PER3 nuclear localization and PER2 degradation. In cycling Rat1 fibroblasts and a mouse model of circadian rhythm, however, PF-4800567 has only a minimal effect on the circadian clock at concentrations substantially over its CK1 IC 50 . This is in contrast to the pan-CK1␦/ inhibitor PF-670462 that robustly alters the circadian clock under similar conditions. These data indicate that CK1 is not the predominant mediator of circadian timing relative to CK1␦. PF-4800567 should prove useful in probing unique roles between these two kinases in multiple signaling pathways.All living things, from fungi to humans, have regular cycles aligning them with the daily events in their environment. These cycles, known as circadian rhythms, are controlled in mammals by the master clock located in the suprachiasmatic nucleus of the hypothalamus (Antle and Silver, 2005;Gallego and Virshup, 2007). At the cellular level, the molecular events behind clock cycling are described by the regular increase and decrease in mRNAs and proteins that define feedback loops, resulting in approximately 24-h cycles. The suprachiasmatic nucleus is primarily regulated, or entrained, directly by light via the retinohypothalamic tract. The cycling outputs of the suprachiasmatic nucleus, not fully identified, regulate multiple downstream rhythms, such as those in sleep and awakening, body temperature, and hormone secretion (Schibler et al., 2003;Ko and Takahashi, 2006). As anyone who has experienced jet lag knows, misalignment of the internal clock with the external environment profoundly affects well being. Furthermore, diseases, such as depression, seasonal affective disorder, and metaArticle, publication date, and citation information can be found at

show abstract

Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Casein Kinase 1ϵ Minimally Alters Circadian Clock Period

Walton

Fisher²,

Rubitski³

et al. 2009

J Pharmacol Exp Ther

155

179

View full text Add to dashboard Cite

show abstract

“…32,39 This effect can be demonstrated by measurement of the enhanced sensitivity to the vasoconstrictor angiotensin II in animals after long-term drug administration at dosages of drug that do not directly affect BP (7 d). 40 As shown in Figure 7, there is an enhanced constrictor response to infused angiotensin II in the presence of a selective COX-2 inhibitor that is not apparent in the presence of an equivalent dosage of a chimeric inhibitor. This lack of hypertension with chimeric NO donor drugs has also been reported with naproxcinod.…”

Section: Chimeric Cyclooxygenase-2 Inhibitorsmentioning

confidence: 94%

Frontiers in Nephrology

Letts¹,

Loscalzo

2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

“…[33][34][35][36] Air pouches were generated based on previously described methods. [37][38][39] Briefly, 8 to 14-week-old females were anesthetized on day 0 and injected with 14 ml of air subcutaneously in the interscapular region to produce a pouch. On day 3, rats were reinjected with 10 ml of air at the same site to boost the pouch.…”

Section: Air Pouch Inductionmentioning

confidence: 99%

The arthritis severity quantitative trait locus Cia7 regulates neutrophil migration into inflammatory sites

et al. 2007

View full text Add to dashboard Cite

Neutrophils are required for the development of arthritis in rodents, and are the predominant cell in the synovial fluid of active rheumatoid arthritis. We hypothesized that neutrophil migration into the inflammed joint is genetically regulated. In addition, this genetic regulation would be accounted for by one of the arthritis loci that we have previously identified in an intercross between arthritis-susceptible DA and arthritis-resistant ACI rats studied for collagen-induced arthritis. We used the synovial-like air pouch model injected with carrageenan, and tested DA, ACI, and four congenic strains. ACI exudates had a significantly lower number of neutrophils compared with DA. Transfer of DA alleles at Cia7 into the ACI background, as in ACI.DA(Cia7) congenics, was enough to increase exudate neutrophil numbers to levels identical to DA, and this locus accounted for the difference between parental strains. None of the other congenic intervals explained the differences in exudate neutrophil counts. In conclusion, we have identified a novel function for Cia7, and determined that it regulates neutrophil migration into a synovial-like inflammatory site. Our data revealed no intrinsic defect in neutrophil responses to chemotactic agents, and suggest that Cia7 regulates an as yet unidentified factor central to neutrophil recruitment into inflammed tissues.

show abstract

Synthesis and Selective Cyclooxygenase-2 Inhibitory Activity of a Series of Novel, Nitric Oxide Donor-Containing Pyrazoles

Cited by 77 publications

References 43 publications

Selective Inhibition of Casein Kinase 1ϵ Minimally Alters Circadian Clock Period

Selective Inhibition of Casein Kinase 1ϵ Minimally Alters Circadian Clock Period

Frontiers in Nephrology

The arthritis severity quantitative trait locus Cia7 regulates neutrophil migration into inflammatory sites

Contact Info

Product

Resources

About