From ergolines to indoles: improved inhibitors of the human H3 receptor for the treatment of narcolepsy.
Ergolines were recently identified as a novel class of H3 receptor (H3R) inverse agonists. Although their optimization led to drug candidates with encouraging properties for the treatment of narcolepsy, brain penetration remained low. To overcome this issue, ergoline 1 ((6aR,9R,10aR)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide)) was transformed into a series of indole derivatives with high H3R affinity. These new molecules were profiled by simultaneous determination of their brain receptor occupancy (RO) levels and pharmacodynamic (PD) effects in mice. These efforts culminated in the discovery of 15 m ((R)-1-isopropyl-5-(1-(2-(2-methylpyrrolidin-1-yl)ethyl)-1H-indol-4-yl)pyridin-2(1H)-one), which has an ideal profile showing a strong correlation of PD effects with RO, and no measurable safety liabilities. Its desirably short duration of action was confirmed by electroencephalography (EEG) measurements in rats.
Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4058 Basel (Switzerland). yves.auberson@novartis.com.
Yves P
YP
Auberson
Thomas
T
Troxler
Xuechun
X
Zhang
Charles R
CR
Yang
Dominik
D
Feuerbach
Yu-Chih
YC
Liu
Bharat
B
Lagu
Mark
M
Perrone
Lijun
L
Lei
Xiaoxia
X
Shen
Dushan
D
Zhang
Chunxiu
C
Wang
Tie-Lin
TL
Wang
Karin
K
Briner
Mark G
MG
Bock
D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004569:Electroencephalography; D004873:Ergolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006633:Histamine Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009290:Narcolepsy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
C000601545:1-isopropyl-5-(1-(2-(2-methylpyrrolidin-1-yl)ethyl)-1H-indol-4-yl)pyridin-2(1H)-one; D004873:Ergolines; D006633:Histamine Antagonists; D007211:Indoles; D011728:Pyridones; D018100:Receptors, Histamine H3
H3 receptor; histamine; indoles; medicinal chemistry; neurotransmitters