Brotschi, Christine; Bolli, Martin H.; Gatfield, John; Heidmann, Bibia; Jenck, Francois; Roch, Catherine; Sifferlen, Thierry; Treiber, Alexander; Williams, Jodi T.; Boss, Christoph published the artcile< From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs>, HPLC of Formula: 85740-98-3, the main research area is insomnia disorders orexin receptor antagonist metabolic stability orally brain; drug design; dual orexin receptor antagonists; insomnia; sleep disorders; structure-activity relationships.
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 inhouse 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 (fu 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)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved in vivo efficacy compared to 6.
ChemMedChem published new progress about Blood proteins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (plasma protein binding). 85740-98-3 belongs to class chlorides-buliding-blocks, and the molecular formula is C8H7ClO3, HPLC of Formula: 85740-98-3.
Referemce:
Chloride – Wikipedia,
Chlorides – an overview | ScienceDirect Topics