“…KYS-05090S also did not mediate inhibition Nav1.5, nor several types of potassium channels that are expressed in the heart, suggesting that this compound may not have any adverse cardiovascular effects (Table 1). Previously published toxicity tests indicate that this compound is well tolerated at doses up to 26 mg/kg intravenously and 250 mg/kg orally [25] nor was there inhibition of cytochrome P (Lee et al, unpublished results) altogether indicating that this compound may hold further promise for clinical development. Interestingly, KYS-05090S has been shown to have an antitumor activity in vivo in mice [31], which fits with the idea that T-type calcium channels may promote tumor growth [9].…”
T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in half-inactivation potential. KYS-05090S was then tested in models of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS-05090S mediates a potent analgesic effect in inflammatory and neuropathic pain through T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.
“…KYS-05090S also did not mediate inhibition Nav1.5, nor several types of potassium channels that are expressed in the heart, suggesting that this compound may not have any adverse cardiovascular effects (Table 1). Previously published toxicity tests indicate that this compound is well tolerated at doses up to 26 mg/kg intravenously and 250 mg/kg orally [25] nor was there inhibition of cytochrome P (Lee et al, unpublished results) altogether indicating that this compound may hold further promise for clinical development. Interestingly, KYS-05090S has been shown to have an antitumor activity in vivo in mice [31], which fits with the idea that T-type calcium channels may promote tumor growth [9].…”
T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in half-inactivation potential. KYS-05090S was then tested in models of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS-05090S mediates a potent analgesic effect in inflammatory and neuropathic pain through T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.
“…Pioneer studies by Jung and colleagues evaluated the antitumor activity of KYS05090 in a mouse lung adenocarcinoma A549 xenograft, which slowed down tumor growth upon intravenous (61) or oral administration (62). Another 3,4dihydroquinazoline able to block TTCC, KYS05047, demonstrated antitumor efficacy in the same xenograft model when administered orally (63).…”
Section: Effects Of Ttcc Blockade/gene Silencing On Tumor Growth: In mentioning
In the past decade, T-type Ca channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, and studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug-drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer..
“…A series of novel carbazolyloxy phenylquinazoline derivatives have been developed as angiotensin converting enzyme (ACE) inhibitors. Amongst them compounds (54)(55)(56) showed maximum inhibitory potency in enzyme based assays. The most potent (54-56) compounds have common active site with the Lisinopril binding site [66].…”
Section: Biological Activities Of Quinazolinone and Quinazoline Derivmentioning
Drug discovery and optimization comprise one of the most significant targets in medicinal chemistry. Quinazoline and quinazolinone derivatives and nitrogencontaining heterocycles have received significant attention due to their widely and distinct biopharmaceutical activities. Quinazolines and quinazolinones are considered as noteworthy chemical for the synthesis of diverse physiological significance and pharmacological utilized molecules. Quinazolines are building blocks for about 150 naturally occurring alkaloids with a broad range of biological activity. The various substituted quinazolines and quinazolinones displayed important, for example, sedative hypnotics, antibacterial, anti-inflammatory, analgesic, antipsychotic, antifungal, antimalarial, anticonvulsant, anti-Parkinsonism, cancer, and other activities. This chapter aims to highlight the latest evidence of quinazolinone and quinazoline derivatives as a privileged scaffold in medicinal chemistry.
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