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A series of alkylamido- ( 1) and alkylaminobiphenyl ( 2) derivatives were synthesized as possible bioisosters of the reported ACAT inhibitors phenylpyridazine analogues ( I). Both 1and 2were tested on the human ACAT-1 and ACAT-2 isoforms. The amino derivatives 2were found to be inactive, contrary to the related pyridazine derivatives. By contrast, the ortho -substituted amides 1aand 1dshowed an interesting activity. These results support the essential role of the pyridazine nucleus. Modeling studies were also performed. [ABSTRACT FROM AUTHOR]

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the 42 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure−activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitrotend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds. [ABSTRACT FROM AUTHOR]