Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.
We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.
Imanishi
Masashi
M
Chemistry Research Laboratories, Pharmacological Research Laboratories, Applied Pharmacology Research Laboratories, Astellas Pharma Inc, Tsukuba-shi, Ibaraki, Japan.
Nakajima
Yutaka
Y
Tomishima
Yasuyo
Y
Hamashima
Hitoshi
H
Washizuka
Kenichi
K
Sakurai
Minoru
M
Matsui
Shigeo
S
Imamura
Emiko
E
Ueshima
Koji
K
Yamamoto
Takao
T
Yamamoto
Nobuhiro
N
Ishikawa
Hirofumi
H
Nakano
Keiko
K
Unami
Naoko
N
Hamada
Kaori
K
Matsumura
Yasuhiro
Y
Takamura
Fujiko
F
Hattori
Kouji
K
D015078:2-Hydroxyphenethylamine / Q000031:analogs & derivatives* / Q000737:chemistry; D000284:Administration, Oral; D000322:Adrenergic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D019817:Benzoic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry*; D001897:Boronic Acids / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000737:chemistry; D004986:Ether / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry*
D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D001713:Biphenyl Compounds; D001897:Boronic Acids; D004852:Epoxy Compounds; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; D004986:Ether; D015078:2-Hydroxyphenethylamine; D019817:Benzoic Acid