Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders.
Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.
LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA. Electronic address: zhongli.gao@sanofi.com.
Zhongli
Z
Gao
William J
WJ
Hurst
Werngard
W
Czechtizky
Dominique
D
Francon
Guy
G
Griebel
Raisa
R
Nagorny
Philippe
P
Pichat
Lothar
L
Schwink
Siegfried
S
Stengelin
James A
JA
Hendrix
Pascal G
PG
George
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004355:Drug Stability; D006168:Guinea Pigs; D000882:Haplorhini; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D011714:Pyrans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism; D012756:Sheep; D020178:Sleep Disorders, Circadian Rhythm / Q000188:drug therapy* / Q000378:metabolism; D013379:Substrate Specificity
D054828:Histamine H3 Antagonists; D011714:Pyrans; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C575741:tetrahydro-pyran-4-carboxylic acid (2-methyl-4-(2-methyl-(1,3')bipyrrolidinyl-1'-yl)phenyl)amide
Awakening; EEG; GPCR; Histamine H(3) receptor antagonist/inverse agonist; Neurotransmitters (acetylcholine, noradrenaline, dopamine, GABA and serotonin)