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

• Published in: Journal of medicinal chemistry Vol. 51; no. 15; pp. 4804 - 4822
• Main Authors: Imanishi, Masashi, Nakajima, Yutaka, Tomishima, Yasuyo, Hamashima, Hitoshi, Washizuka, Kenichi, Sakurai, Minoru, Matsui, Shigeo, Imamura, Emiko, Ueshima, Koji, Yamamoto, Takao, Yamamoto, Nobuhiro, Ishikawa, Hirofumi, Nakano, Keiko, Unami, Naoko, Hamada, Kaori, Matsumura, Yasuhiro, Takamura, Fujiko, Hattori, Kouji
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 14-08-2008
• Subjects: Biological and medical sciences; Catecholaminergic system; General and cellular metabolism. Vitamins; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Agonist; Intravenous administration; Rat; Monkey; Selectivity; Benzoic acid derivatives; Structure activity relation; Chlorine Organic compounds; Primates; Chemical synthesis; Dog; Human; Fissipedia; Carnivora; Aminoalcohol; Ether; Rodentia; β3-Adrenergic receptor; Oral administration; Bioavailability; Naphthalene derivatives; In vitro; Vertebrata; Mammalia; Biphenyl derivatives; Animal; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800222k

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.