Strategies and Structure-Activity Advances

An early biphenyl candidate, A-331440 (6) has been reported to be a competitive, potent inverse agonist with balanced activity at human and rat H3Rs with good oral bioavailability [40]. While A-331440 was active in obesity models, its development was precluded by genotoxicity issues [41], The latter was eliminated by a tactical orf/zo-substitution on the phenoxy central core by fluorine to provide A-417022 (7). A-417022 and the 3,5-difluoro analog (A-423579) also produced prolonged weight loss over a 28-day period in a rat diet-induced obesity model [17,41], 

BF-2649 (18) is a potent and selective H3 antagonist reportedly in clinical trials for a number of potential indications, including cognitive enhancement, appetite 

A series of diamine amides based on the phenoxypropyl amine scaffold was reported. Amide 26 displayed an hH3 Ki of 1 nM and was selective versus other histamine receptors [73]. The chirality was removed via cyclic diamines to produce tetrahydroisoquinolines, tetrahydroquinolines, benzazepines and indolines [74]. The benzazepine 27 displayed picomolar hH3 binding affinity. Pharmacokinetic issues were also identified with this diamine series, with i.v. half-lives of 10-12 h in the rat. A strategy to remove the diamine skeleton and prepare new H3 

A series of piperazine-based antagonists was disclosed as potential obesity agents [77]. Compound 30 shows an hH3R K of 11 nM. Quinazolone 31 was highlighted, and may be of further interest as the specific synthesis and a crystal structure was disclosed [78]. 

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