Identification and Structure–Activity Studies of Novel Ultrashort-Acting Benzodiazepine Receptor Agonists

Retrometabolism‐Based Drug Design and Targeting

“…A set of soft benzodiazepines were developed originally by GlaxoSmithKline on the basis of the remifentanil experience, and were intended as i.v. agent with a predictable fast-onset, short duration of action, and rapid recovery profile [367,368]. They are soft analogs of diazepam (161), bromazepam (162), or midazolam (163), and several ester-containing side chains at the 3-position were explored.…”

“…A number of them maintained high binding affinity at the benzodiazepine receptor (<50 nM), showed good (>100-fold) separation of activity between the (active) ester and the (inactive) acid, and were able to cause loss of the righting reflex (LRR) in rats, an effect associated with benzodiazepine full agonism. Structures such as CNS 7259X (164) [367,369] and CNS 7056 (166) [368,370] (Fig. 37) were selected for development, which has been taken over by CeNeS and later PAION.…”

Copper-catalyzed ligand-free amidation of aryl iodides and amino acid amides to synthesize C3-(Z)-1H-benzo[e][1,4]diazepin-2(3H)-ones

“…B Gang Liu gangliu27@tsinghua.edu.cn 1 structure, the 1,4-benzodiazepine-2-one (1,4-BZD) scaffold exhibits many kinds of biological activities, such as hypnosis, sedation, and muscle relaxation, [2,3]. Recent investigations [4][5][6][7] indicated that a C3-chiral side chain in 1,4-BZDs is essential for their action on the corresponding biological targets, such as ultra short-acting benzodiazepine receptor agonism [4], BACE-1 inhibition [5], cysteine protease inhibition [6], and antitumor proliferation [7] (Fig. 1).…”

“…Recently, a Cu-catalyzed selective amidation of aryl [1,4]diazepin-2(3H)-ones halides and amino acid amides was discovered by the Zeng group (note: the selective amidation of aryl halides and amino acid amides via Cu-catalyzation was recently reported by Dong et al [18]. ), and a series of linear aryl-substituted amino acid amides were prepared using Zeng's method.…”

“…), and a series of linear aryl-substituted amino acid amides were prepared using Zeng's method. Herein, we developed a novel synthetic methodology for the synthesis of (Z)-1H-benzo[e] [1,4]diazepin-2(3H)-ones with high enantioselectivity at the C3-position. Our method involves the one-pot ligand-free Cu-catalyzed selective amidation of 2-iodo-phenylketone by amino acid amides, followed by an intramolecular dehydration.…”