Structure–activity relationship analysis identified (+)-N-(3-aminopropyl)-N-1-(5-benzyl-3-methyl-4-oxo-1,2thiazolo5,4-dpyrimidin-6-yl)-2-methylpropyl-4-methylbenzamide (AZD4877), from a series of ...novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
We have designed and synthesized new 5-lipoxygenase inhibitors, fluorinated 3,4-dihydroxychalcones, and evaluated their biological activities with respect to antiperoxidation activity and in vitro ...antitumor activities. All fluorinated chalcones tested showed 5-lipoxygenase inhibition on rat basophilic leukemia-1 (RBL-1) cells and inhibitory action on Fe
3+-ADP induced NADPH-dependent lipid peroxidation in rat liver microsomes. The potencies were comparable or better to that of the lead 3,4-dihydroxychalcone. 6-Fluoro-3,4-dihydroxy-2′,4′-dimethoxy chalcone (
7) was the most effective compound in the in vitro assay using a human cancer cell line panel (HCC panel) consisting of 39 systems.
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Oxidation of dopa and dopamine requires a net removal six electrons to produce indolequinones, the monomeric precursors of eumelanin pigment. On the other hand, their 6-fluoroderivatives suffer only ...four-electron oxidation to yield the same products (M. E. Rice, B. Mogaddam, C. R. Creveling, and K. L. Kirk, Anal. Chem. 59, 1534–1536, 1987). Taking advantage of this novel fluorochemistry, we reexamined the oxidative mechanism of 3,4-dihydroxyphenylacetic acid and 6-fluoro-3,4-dihydroxyphenylacetic acid to throw more light on the nature of reactive intermediates formed during the reaction. Enzymatic or chemical oxidation of 3,4-dihydroxyphenylacetic acid generated the transient o-quinone which exhibited rapid intramolecular cyclization and side chain modification to produce 2,5,6-trihydrobenzofuran and 3,4-dihydroxymandelic acid, respectively. However, when 6-fluoro-3,4-dihydroxyphenylacetic acid was oxidized either by tyrosinase or by sodium periodate, the resultant quinone uniquely exhibited only cyclization coupled with loss of fluoride ion. This clean reaction allowed us to establish the structures of the transient reactive intermediates. Two interconvertable isomeric forms of the product were isolated and characterized from the reaction mixture. If the oxidation was carried out in water, a yellow quinolactone accumulated in the reaction mixture. This compound was instantaneously converted to a purple quinone methide upon addition of a trace amount of sodium phosphate. Passage through a C18 HPLC column caused the reverse transformation. The structures of these products were established by semiempirical molecular orbital calculations and NMR spectrometry. Comparison of the oxidation mechanisms of melanin precursors, dopa and dopamine, with that of 3,4-dihydroxyphenylacetic acids reveals that a similar quinone methide intermediate is likely to be formed during eumelanin biosynthesis.
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel ...activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Background: There is a dearth of studies to assess the effectiveness of cryotherapy as a possible adjuvant in anesthesia. Therefore, this study aimed to compare the impact of pretreatment intraoral ...ice packs, application of Endo-ice, and a combination of Endo-ice and intrapulpal ice sticks use on the effectiveness of pulpal anesthesia as an adjunct in the management of pain and dental anxiety in mandibular second molars with symptomatic irreversible pulpitis (SIP) against traditional inferior alveolar nerve block (IANB) technique. Materials and methods: The randomized controlled double-blind clinical study comprised of 200 subjects within the age group of 20-45 years with SIP involving mandibular second molars and divided into four groups of 50 each. Conventional IANB was administered in group 1. Intraoral compact ice packs, Endo-ice, and combined use of Endo-ice and intrapulpal ice sticks were employed following conventional IANB in groups 2, 3, and 4, respectively. The intensity of pain and anxiety before and after the intervention was documented using Heft-Parker visual analog scale (HP-VAS) and Corah's Dental Anxiety Scale-Revised (DAS-R). Results: The average age of the overall study sample was 30.8±2.08 years, and the differences in age and gender distribution were found to be statistically insignificant. The mean HP-VAS scores on access opening and pulpectomy, using ANOVA paired with Tukey's post hoc multiple comparison tests were evaluated to be statistically highly significant (p<0.001). The greatest reduction in HP-VAS score was observed in group 4 receiving combined use of both Endo-ice and intrapulpal ice sticks. While the pretreatment DAS-R score was determined to be statistically insignificant between groups, group 1 subjects had the highest DAS-R score postoperatively (p<0.001). The effectiveness of pulpal anesthesia was found to be 84%, 96%, 92%, and 98% for groups 1 through 4, respectively, and demonstrated a statistically significant difference. Conclusion: The combined use of Endo-ice and intrapulpal ice sticks used as an adjuvant to local anesthesia (LA) was found to be significantly effective in lowering pain compared to the control groups in molars with SIP. Cold administration before and during the procedure was more effective than conventional LA in lowering intraoperative anxiety. Furthermore, the use of Endo-ice and intrapulpal cold after IANB significantly improves the effectiveness of pulpal anesthesia in mandibular second molars with SIP.
