Synthesis of a novel series of benzocycloalkene derivatives as melatonin receptor agonists.
We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding affinities to melatonin receptors. To control the spatial position of the amide group, one of the important pharmacophores, we incorporated an endo double bond, an exo double bond (E- and Z-configurations), and a chiral center (R- and S-configurations) at position 1. The indan derivatives with the S-configuration at position 1 were the most promising in terms of potency and selectivity for the human melatonin receptor (MT(1) site), while compounds with the R-configuration showed little potential. Our next attempt was to investigate the most favorable conformation of the methoxy group, the other important pharmacophore for binding to the MT(1) receptor. The introduction of a methyl group at position 5 of the indene ring conserved affinity; however, at position 7, it caused a decrease in affinity. These results suggested that the substitution at position 7 forced the methoxy group to adopt an unfavorable orientation. The optimization of the condensed ring size and substituents led to (S)-8d [(S)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]propionamide], which had high affinity for the human MT(1) receptor (K(i) = 0.041 nM) but no significant affinity for the hamster MT(3)receptor (K(i) = 3570 nM). In addition, a practical synthetic method of chiral N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]alkanamides employing asymmetric hydrogenation with (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ru has been established.
Fukatsu
Kohji
K
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
Uchikawa
Osamu
O
Kawada
Mitsuru
M
Yamano
Toru
T
Yamashita
Masayuki
M
Kato
Koki
K
Hirai
Keisuke
K
Hinuma
Shuji
S
Miyamoto
Masaomi
M
Ohkawa
Shigenori
S
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000378:metabolism*; D008647:Mesocricetus; D009928:Organ Specificity; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000819:agonists*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D044094:Receptors, Melatonin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D007192:Indenes; C465771:N-(2-(2,3-dihydro-6-methoxy-1H-inden-1yl)ethyl)propionamide; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D008550:Melatonin