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.
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Imanishi M, Nakajima Y, Tomishima Y, Hamashima H, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K
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.
J Med Chem. 2008 Aug 14;51(15):4804-22. doi: 10.1021/jm800222k. Epub 2008 Jul 24.
- PubMed ID
- 18651730 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Isoprenaline Beta-1 adrenergic receptor EC 50 (nM) 0.084 N/A N/A Details Isoprenaline Beta-3 adrenergic receptor EC 50 (nM) 0.97 N/A N/A Details