- Discovery of a novel series of benzoic acid derivatives as potent and selective human β3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety
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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 β3, high selectivity over β1 and β2, and good pharmacokinetic properties in rats, dogs, and monkeys.
- Imanishi, Masashi,Nakajima, Yutaka,Tomishima, Yasuyo,Hamashima, Hitoshi,Washizuka, Kenichi,Sakurai, Minora,Matsui, Shigeo,Imamura, Emiko,Ueshima, Koji,Yamamoto, Takao,Yamamoto, Nobuhiro,Ishikawa, Hirofumi,Nakano, Keiko,Unami, Naoko,Hamada, Kaori,Matsumura, Yasuhiro,Takamura, Fujiko,Hattori, Kouji
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- Alternative synthesis of the chiral atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation
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We have developed an alternative synthesis of the atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A. Two key intermediates have been synthesised involving enantioselective hydrogenation of an aminoketone and an enamide providing the corre
- Devocelle, Marc,Mortreux, Andre,Agbossou, Francine,Dormoy, Jean-Robert
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p. 4551 - 4554
(2007/10/03)
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