RESUMO
The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid use, and this can be treated with a localized drug distribution of a non-CNS penetrant, peripherally restricted opioid receptor antagonist. Herein, we describe the application of Theravance's multivalent approach to drug discovery coupled with a physicochemical property design strategy by which the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl carboxamide series of µ-opioid receptor antagonists was optimized to afford the orally absorbed, non-CNS penetrant, Phase 3 ready clinical compound axelopran (TD-1211) 19i as a potential treatment for opioid-induced constipation.
RESUMO
The environment of the CuI ion in the distal ligand group decides the fate of the reduction of O2 by the two analogues 1 and 2 of the heme a3 CuB center in cytochrome c oxidase. The fourfold coordination by N in 1 favors the CuII oxidation state and leads to a 4 e- -4 H+ reduction and the formation of H2 O under physiological conditions, while with 2 a 2 e- -2 H+ reduction occurs to form the cytotoxic H2 O2 .
