Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists.
To develop a new therapeutic agent for sleep disorders, we synthesized a novel series of tricyclic indan derivatives and evaluated them for their binding affinity to melatonin receptors. In our previous paper, we proposed a conformation of the methoxy group favorable for the binding of the MT(1) receptor. To fix the methoxy group in an active conformation, we decided to synthesize conformationally restricted tricyclic indan analogues with the oxygen atom in the 6-position incorporated into a furan, 1,3-dioxane, oxazole, pyran, morpholine, or 1,4-dioxane ring system. Among these compounds, indeno[5,4-b]furan analogues were found to be the most potent and selective MT(1) receptor ligands and to have superior metabolic stability. The optimization of substituents led to (S)-(-)-22b, which showed very strong affinity for human MT(1) (K(i) = 0.014 nM), but no significant affinity for hamster MT(3)() (K(i) = 2600 nM) or other neurotransmitter receptors. The pharmacological effects of (S)-(-)-22b were studied in experimental animals, and it was found that a dose of 0.1 mg/kg, po promoted a sleep in freely moving cats, as demonstrated by a decrease in wakefulness and increases in slow wave sleep and rapid eye movement sleep, which lasted for 6 h after administration. Melatonin (1 mg/kg, po) also had a sleep-promoting effect, though it lasted only 2 h. A new chiral method for the synthesis of (S)-(-)-22b starting from 60, which was prepared from 59 employing asymmetric hydrogenation with the (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ru complex, was developed. (S)-(-)-22b (TAK-375) is currently under clinical trial for the treatment of insomnia and circadian rhythm disorders.
Uchikawa
Osamu
O
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. uchikawa_osamu@takeda.co.jp
Fukatsu
Kohji
K
Tokunoh
Ryosuke
R
Kawada
Mitsuru
M
Matsumoto
Kiyoharu
K
Imai
Yumi
Y
Hinuma
Shuji
S
Kato
Koki
K
Nishikawa
Hisao
H
Hirai
Keisuke
K
Miyamoto
Masaomi
M
Ohkawa
Shigenori
S
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002415:Cats; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D008647:Mesocricetus; D008958:Models, Molecular; D009928:Organ Specificity; D010902:Pituitary Gland / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D044094:Receptors, Melatonin; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014851:Wakefulness / Q000187:drug effects
D007189:Indans; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D000242:Cyclic AMP; D008550:Melatonin