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From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs
Author(s) -
Brotschi Christine,
Bolli Martin H.,
Gatfield John,
Heidmann Bibia,
Jenck Francois,
Roch Catherine,
Sifferlen Thierry,
Treiber Alexander,
Williams Jodi T.,
Boss Christoph
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900618
Subject(s) - in vivo , antagonist , orexin , pharmacology , chemistry , insomnia , receptor , stereochemistry , medicine , biochemistry , biology , microbiology and biotechnology , neuropeptide
The orexin system is responsible for regulating the sleep‐wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5‐methoxy‐4‐methyl‐2‐[1,2,3]triazol‐2‐yl‐phenyl)‐{(S)‐2‐[5‐(2‐trifluoromethoxy‐phenyl)‐[1,2,4]oxadiazol‐3‐yl]‐pyrrolidin‐1‐yl}methanone ( 6 ), a compound which emerged from our in‐house research program. Compound 6 was shown to be a potent, brain‐penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above‐mentioned shortcomings resulted in the identification of (4‐chloro‐2‐[1,2,3]triazol‐2‐yl‐phenyl)‐{(S)‐2‐methyl‐2‐[5‐(2‐trifluoromethoxy‐phenyl)‐4 H ‐[1,2,4]triazol‐3‐yl]‐pyrrolidin‐1‐yl}l‐methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .