Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators

NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

“…The 200 mg dose level showed a less than expected increase in values. The observed peak NGP 555 concentration level for the three dosing levels (100, 200, and 400 mg, respectively) occurred at 3.9, 4.1, 5.0 hours 37 or Ab 38 versus Ab 42 from baseline to day 14 in humans. CSF was collected by serial sampling at baseline (day 1) and day 14 (10 hours after dose) after dosing with NGP 555 200 mg (4 subjects), NGP 555 400 mg (2 subjects), or placebo (2 subjects).…”

“…Although GSMs represented a minority of the molecules tested in the clinic [16], to date most of these candidates have not succeeded because of compound toxicity based on structure or limited effectiveness to lower cerebrospinal fluid (CSF) amyloid biomarkers [32][33][34]. However, several GSMs are currently on the horizon and new discoveries of optimal chemical structures carry hope for the future of GSMs as therapeutics for AD [35][36][37][38][39][40][41][42][43][44]. One such molecule is NGP 555, with previous studies demonstrating the ability to favorably alter amyloid biomarkers and pathology in the brain while preventing cognitive decline preclinically.…”

Synthesis and fluorescence of triazoloazines derivatives

“…Êëþ÷îâ³ ñëîâà: òð³àçîëîàçèíè, ôëþîðåñöåíö³ÿ, ôëþîðåñöåíòíèé çîíä, âèçíà÷åííÿ âîäè, ñèíòåç. DOI: 10.32434/0321-4095-2019-126-5-71-76 Âñòóï Ïîõ³äí³ [1,2,4]òð³àçîëî [1,5-a]ï³ðèäèíó òà ñïîð³äíåíèõ ñèñòåì òð³àçîëîàçèí³â ³íòåíñèâíî âèâ÷àþòüñÿ â îñòàíí³ ðîêè ó çâ'ÿçêó ç â³äêðèòòÿì ñåðåä íèõ ñïîëóê ç âèñîêèì ð³âíåì á³îëîã³-÷íî¿ àêòèâíîñò³. Çîêðåìà, ñòðóêòóðíèé ôðàãìåíò [1,2,4]òð³àçîëî [1,5-a]ï³ðèäèíó º îñíîâîþ ñïîëóê, ÿê³ òåñòóþòüñÿ äëÿ ë³êóâàííÿ çàõâîðþâàíü ð³çíî¿ åò³îëî㳿 [1][2][3].…”

“…DOI: 10.32434/0321-4095-2019-126-5-71-76 Âñòóï Ïîõ³äí³ [1,2,4]òð³àçîëî [1,5-a]ï³ðèäèíó òà ñïîð³äíåíèõ ñèñòåì òð³àçîëîàçèí³â ³íòåíñèâíî âèâ÷àþòüñÿ â îñòàíí³ ðîêè ó çâ'ÿçêó ç â³äêðèòòÿì ñåðåä íèõ ñïîëóê ç âèñîêèì ð³âíåì á³îëîã³-÷íî¿ àêòèâíîñò³. Çîêðåìà, ñòðóêòóðíèé ôðàãìåíò [1,2,4]òð³àçîëî [1,5-a]ï³ðèäèíó º îñíîâîþ ñïîëóê, ÿê³ òåñòóþòüñÿ äëÿ ë³êóâàííÿ çàõâîðþâàíü ð³çíî¿ åò³îëî㳿 [1][2][3]. Íàéá³ëüø øèðîêå çàñòîñóâàííÿ â àíàë³òè÷í³é õ³ì³¿ òð³àçîëüí³ ôðàãìåíòè çíàéøëè ÿê êîìïëåêñîóòâîðþâàëüí³ ë³íêåðè, ùî ïðè-ùåïëåí³ äî ôëþîðåñöåíòíîãî ÿäðà, äëÿ âèçíà-÷åííÿ âàaeêèõ ìåòàë³â, çîêðåìà ³îí³â Cu 2+ [4,5], Zn 2+ , Fe 3+ [6] òà Sn 2+ [7].…”

“…Îïèñàíî âèêîðèñòàííÿ êîíäåíñîâàíîãî áàðâíèêà íà îñ-íîâ³ òð³àçîëó äëÿ á³îâ³çóàë³çàö³¿ ðîçïîä³ëó ãë³êîêîí'þãàòó ó êë³òèí³ [9]. Ç îãëÿäó íà ñòðóêòóðí³ îñîáëèâîñò³, íîâ³ çàì³ùåí³ â ïåð³-ïîëîaeåííÿõ àì³íî-ã³äðîêñèïîõ³äí³ êîíäåíñîâàíèõ [1,2,4]òð³-àçîëîàçèí³â ìîaeóòü ïðîÿâëÿòè âëàñòèâîñò³, ïðè-òàìàíí³ ëþì³íåñöåíòíèì çîíäàì, ³ ìàòè ïåðñïåêòèâè âèêîðèñòàííÿ â ïðàêòèö³ àíàë³çó.…”