Biomedical subjects
Nick Clayton
Publications and source records attributed to Nick Clayton.
Identification of novel pyrazole acid antagonists for the EP1 receptor.
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.
Vanilloid receptor 1 expression in human tooth pulp in relation to caries and pain.
AIMS: To investigate the presence of vanilloid receptor 1 (TRPV1) in human dental pulp and to correlate any expression with caries and pain. METHODS: Permanent mandibular first molars were collected and categorized as intact or grossly carious. Grossly carious teeth were further categorized as carious asymptomatic or carious painful samples. Coronal pulps were removed and processed for indirect immunofluorescence using antibodies raised against TRPV1 and a neuronal marker, either protein gene product 9.5 or alpha-smooth muscle actin, in conjunction with Ulex europaeus agglutinin 1 lectin to fully label the pulp vasculature. RESULTS: Analysis revealed that TRPV1 labeling was not confined to pulpal nerve fibers. TRPV1 was also consistently expressed within pulp microvasculature. Expression of neuronal TRPV1 was significantly increased throughout the pulp in grossly carious samples (P < .05). No significant differences were found between carious asymptomatic and carious painful samples. A significant increase in vascular TRPV1 expression was observed in arterioles present in the midcoronal pulp in carious painful compared with carious asymptomatic samples (mean area +/- SEM [%] of TRPV1 to vascular labeling; 6.48% +/- 4.5% for carious asymptomatic teeth, n = 9; 31.21% +/- 9.6% for carious painful teeth, n = 9; P = .02). CONCLUSION: Expression of TRPV1 in pulpal nerve fibers undergoes marked changes with caries. This may be of relevance in the development of pulpal inflammation, but its relationship to dental pain is still unclear. However, vascular TRPV1 expression does appear to be positively correlated with dental pain, thus providing new insights into symptomatic pulpitis.
The cyclooxygenase-2 inhibitor GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] is effective in animal models of neuropathic pain and central sensitization.
The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.
Identification of 2,3-diaryl-pyrazolo[1,5-b]pyridazines as potent and selective cyclooxygenase-2 inhibitors.
GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.
Control of FMD by vaccination.
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