Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists |
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Authors: | Perrey David A Gilmour Brian P Runyon Scott P Thomas Brian F Zhang Yanan |
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Institution: | Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA |
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Abstract: | As a part of our program to develop OX1-CB1 bivalent ligands, we required a better understanding of the basic structure-activity relationships (SARs) of orexin antagonists. A series of SB-334867 analogues were synthesized and evaluated in calcium mobilization assays. SAR results suggest that the 2-methylbenzoxazole moiety may be replaced with a disubstituted 4-aminophenyl group without loss of activity and an electron-deficient system is generally preferred at the 1,5-naphthyridine moiety for OX1 antagonist activity. In particular, substitution of larger potential linkers such as n-hexyl provided compound 33 with equivalent activity at the OX1 receptor compared to the lead compound SB-334867. These compounds should be of value in the development of ligands targeting the orexin-1 receptor and its potential heterodimers. |
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Keywords: | Orexin Antagonist SB-334867 Structure-activity relationships |
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