Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core |
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Authors: | Dyck Brian Grigoriadis Dimitri E Gross Raymond S Guo Zhiqiang Haddach Mustapha Marinkovic Dragan McCarthy James R Moorjani Manisha Regan Collin F Saunders John Schwaebe Michael K Szabo Tomas Williams John P Zhang Xiaohu Bozigian Haig Chen Ta Kung |
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Institution: | Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, California 92130, USA. bdyck@neurocrine.com |
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Abstract: | Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo2,3-b]pyridine and 1H-pyrazolo3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain (brain]/plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses. |
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