Design and Synthesis of a Potent and Selective Triazolone-Based Peroxisome Proliferator-Activated Receptor α Agonist

Xu, Yanping; Mayhugh, Daniel R.; Saeed, Ashraf; Wang, Xiaodong; Thompson, Richard C.; Dominianni, Samuel J.; Kauffman, Raymond F.; Singh, Jyoti; Bean, James S.; Bensch, William R.; Barr, R. J.; Osborne, John; Montrose‐Rafizadeh, Chahrzad; Zink, Richard W.; Yumibe, Nathan; Huang, Naijia; Luffer‐Atlas, Debra; Rungta, Deepa; Maise, Dale E.; Mantlo, Nathan B.

doi:10.1021/jm034173l

Cited by 69 publications

(55 citation statements)

References 23 publications

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“…Although fenobric acid (Willson et al, 2000) does not demonstrate analgesic efficacy after acute administration (Table 1), other fibrates as well as new classes of high-affinity PPAR-␣ ligands have become available (Xu et al, 2003;Singh et al, 2005). These include dual PPAR-␣/PPAR-␥ modulators (Fagerberg et al, 2005) that, by combining the analgesic and antiinflammatory activity of PPAR-␣ with the glucose-lowering properties of PPAR-␥, might offer an innovative therapeutic approach to painful diabetic neuropathies, a condition that afflicts more than 30 million people worldwide.…”

Section: Discussionmentioning

confidence: 99%

Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-α

LoVerme

Russo²,

Rana³

et al. 2006

J Pharmacol Exp Ther

292

320

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Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-␣ (peroxisome proliferator-activated receptor-␣) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-␣ agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and palmitoylethanolamide (PEA) reduced nocifensive behaviors elicited in mice by intraplantar (i.pl.) injection of formalin or i.p. injection of magnesium sulfate. These effects were absent in PPAR-␣-null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcriptionindependent mechanism. Consistent with this hypothesis, blockade of calcium-operated IK ca (K Ca 3.1) and BK ca (K Ca 1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR-␣ agonists may inhibit nocifensive responses by acting on peripheral PPAR-␣. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-␣ was expressed in dorsal root ganglia neurons of wildtype but not PPAR-␣-null mice; and (ii) GW7647 and PEA prevented formalin-induced firing of spinal cord nociceptive neurons in rats. In addition to modulating nociception, GW7647 and PEA reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain; these effects were also contingent on PPAR-␣ expression and were observed following either acute or subchronic PPAR-␣ agonist administration. Finally, acute administration of GW7647 and PEA reduced hyperalgesic responses in the complete Freund's adjuvant and carrageenan models of inflammatory pain. Our results suggest that PPAR-␣ agonists may represent a novel class of analgesics.Current therapies do not control safely and effectively severe pain states-a broad spectrum of debilitating conditions that comprises acute, persistent inflammatory, and neuropathic pain. Even widely used drugs, such as opiates (e.g., morphine) or anticonvulsants (e.g., gabapentin), are only active in a fraction of the patient population and produce multiple, often serious, side effects. Thus, despite continuing progress in analgesic drug discovery, the need for therapeutic agents capable of blocking abnormal pain sensation without impairing normal abilities remains largely unmet.PPAR-␣ is a nuclear receptor that serves important functions in lipid nutrient utilization and inflammation (Taylor et al., 2002;Kostadinova et al., 2005). Like other members of the nuclear receptor superfamily, PPAR-␣ is activated

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Section: Discussionmentioning

confidence: 99%

Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-α

LoVerme

Russo²,

Rana³

et al. 2006

J Pharmacol Exp Ther

292

320

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“…In fact, a recent publication showed that a potent and selective PPAR␣ agonist, LY-518674 (Xu et al, 2003), in patients with low HDLc and high triglycerides or high LDLc had essentially the same effect as fenofibrate in modulating lipid levels, with a similar level of safety concerns (Nissen et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Novel Peroxisome Proliferator-Activated Receptor α Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist

Mukherjee¹,

Locke²,

Miao³

et al. 2008

J Pharmacol Exp Ther

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The first generation peroxisome proliferator-activated receptor (PPAR) ␣ agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPAR␣ agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPAR␣-selective agonists, [[5-[[2-(4-, that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPAR␣ than human PPAR␣; therefore, they were tested in PPAR␣-humanized mice that do not express murine PPAR␣ but express human PPAR␣ selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPAR␣ in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPAR␣ agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.Cardiovascular disease is the leading cause of death for adults in the United States and other developed countries.High low-density lipoprotein-cholesterol (LDLc) and triglycerides and low high-density lipoprotein-cholesterol (HDLc) are prominent risk factors for atherosclerosis. Although considerable progress has been made in lowering LDL-cholesterol by therapeutic means (especially with statins), atherosclerosis still remains a leading cause of mortality. Several clinical studies such as the Scandinavian Simvastatin Survival Study (4S) Group (1994) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group (1998) indicate the benefit of lowering LDLc (Linsel-Nitschke and Tall, 2005). Moderate lifelong reduction in LDLc levels in patients with a mutation in the proprotein convertase 1

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“…1,2,4-Триазол-3-оны представляют интерес, главным образом, как фармакологически значи-мые соединения, активность которых зависит от характера заместителей у атомов N-2, N-4 и C-5 [1][2][3][4]. Среди них обнаружены вещества с противоопухолевыми свойствами [1], агонисты PPAR рецепторов [2] и антагонисты нейрокинина 1 (NK 1 ) [3].…”

Section: Introductionunclassified

“…Среди них обнаружены вещества с противоопухолевыми свойствами [1], агонисты PPAR рецепторов [2] и антагонисты нейрокинина 1 (NK 1 ) [3]. 2,5-Биарил-1,2,4-триазол-3-оны и 4,5-биарил-1,2,4-триазол-3-оны известны как активаторы калиевых (Maxi-K2) каналов [4].…”

Section: Introductionunclassified

Synthesis of functionally substituted of 5-aryl-1,2,4-triazol-3-ones.

Толкунов¹,

Smirnova²,

Tolkunov³

et al. 2017

Chemical

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Разработан метод получения разнозамещенных 5-арил-1,2,4-триазол-3-онов, термической цикли-зацией амидразонов, получаемых in situ из метил бензимидатов и метилкарбазата. Предложена оп-тимальная методика восстановления нитрофенилтриазолонов сульфидом натрия в диоксане. Соот-ветствующие аминоарилтриазолоны получены с выходами 74-76 %.Карбоксипроизводные фенилтриазолонов синтезировали карбонилированием бромфенилтриазо-лонов окисью углерода в присутствии [1,1'-бис(дифенилфосфино)ферроцен]дихлорпалладия (II) (Pd(dppf)Cl 2 ) и триэтиламина в метаноле. Показано что, окисление толилтриазолона перманганатом калия в щелочной среде сопровождается деструкцией триазолонового цикла и приводит к терефта-левой кислоте. Полученные аминофенил-и карбоксифенил-1,2,4-триазол-3-оны представляют инте-рес в плане изучения биологической активности, а также для дальнейшей химической модификации.Ключевые слова: циклизация, карбонилирование, 5-арил-1,2,4-триазол-3-оны, метил карбазат, метил арилкарбоксиимидаты, [1,1'-бис(дифенилфосфино)ферроцен]дихлорпалладий (II). Цель настоящего исследования -разработка методов синтеза 5-арил-1,2,4-триазол-3-онов, содержащих в арильном кольце амино-и карбоксигруппы, легко поддающиеся дальнейшей химической модификации.В настоящее время для получения 5-арил-1,2,4-триазол-3-онов предложено несколько общих синтетических подходов. Это окислительная циклизация семикарбазидов арилальдегидов (1) [6,7], а также щелочная циклизация ацилсемикарбазидов (2) (схема 1) [8,9]. Схема 1Первый метод неудобен тем, что исходные семикарбазоны (1) трудно растворимы практиче-ски во всех органических растворителях и поэтому наработка значительных количеств триазо-лонов (3) труднодостижимая задача. Щелочная циклизация ацилсемикарбазидов (2) зависит от заместителей в бензольном кольце и проходит, как правило, с выходами 10-30 % [8], редко до 50 % [9]. Побочный процесс в этом методе -гидролиз семикарбазидов (2) до соответствующих бензойных кислот. Обсуждение результатовДля синтеза целевых арилтриазолонов (7a-e) использовалась термическая циклизация амид-разонов (6), получаемых in situ из метил бензимидатов (5) и метилкарбазата (схема 2). Перво-* Институт физико-органической химии и углехимии им. Л.М. Литвиненко НАН Украины

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Design and Synthesis of a Potent and Selective Triazolone-Based Peroxisome Proliferator-Activated Receptor α Agonist

Abstract: A new series of hPPARalpha agonists containing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described leading to the discovery of 5 (LY518674), a highly potent and selective PPARalpha agonist.

Cited by 69 publications

References 23 publications

Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-α

Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-α

Novel Peroxisome Proliferator-Activated Receptor α Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist

Synthesis of functionally substituted of 5-aryl-1,2,4-triazol-3-ones.

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