ブレクスピプラゾール 化學(xué)特性,用途語,生産方法
効能
統(tǒng)合失調(diào)癥治療薬
商品名
レキサルティ (大塚製薬)
説明
Brexpiprazole is a novel
antipsychotic drug which serves as a serotonin ® dopamine
activity modulator and has demonstrated efficacy as an
adjunctive treatment in patients with major depressive disorder
(MDD). The drug exhibits a unique pharmacological profile,
acting as a partial agonist of serotonin 5-HT1A and dopamine
D2 receptors and as a full antagonist of 5-HT2A and
noradrenaline α1B/2C receptors, with similar subnanomolar
binding affinity. The drug, which was developed by Otsuka
and Lundbeck, was approved in 2015 by the FDA for the
treatment of schizophrenia and as an adjunctive treatment for
depression. Brexpiprazole is widely considered to be a
successor to Otsuka’s antipsychotic drug aripiprazole (trade
name Abilify) whose patent expired in August 2014.
使用
Brexpiprazole is a kind of atypical antipsychotic. It is a dopamine D2 receptor partial agonist. As a novel serotonin-dopamine activity modulator, it can be used for the treatment of schizophrenia, and for the adjunctive treatment for depression. It can also provide efficacy and tolerability over established adjunctive treatments formajor depressive disorder(MDD).Recent study has also suggested it can ameliorate PCP-induced cognitive deficits in mice via 5-HT1A receptors.
定義
ChEBI: Brexpiprazole(913611-97-9) is a N-arylpiperazine. It is a novel D2 dopamine and serotonin 1A partial agonist, called serotonin-dopamine activity modulator (SDAM), and a potent antagonist of serotonin 2A receptors, noradrenergic alpha 1B and 2C receptors. Brexpiprazole is a drug candidate useful in treatment and prevention of mental disorders including CNS disorders.
合成
Commercially available fluorobenzaldehyde (60) underwent
a substitution reaction with commercial tert-butyl piperazine-1-
carboxylate (61) under basic conditions to afford the
piperazinyl benzaldehyde 62 in excellent yield. Next, the
construction of the benzothiophene was affected by initial
condensation of thioglycolic acid ethyl ester 63 with ochlorobenzaldehyde
62 under mildly basic conditions at
elevated temperatures. Treatment with aqueous base and
adjustment of pH to roughly 5 through the use of 4 N HCl
furnished the 2-carboxylic acid benzothiophene 64 in 80% yield
across the three-step operation. Next, decarboxylation through
the use of cuprous oxide using conditions slightly modified
from those originally described by Goosen followed by acidic
removal of the Boc protecting group on the terminal piperazine
nitrogen secured the key piperazinyl benzothiophene subunit
65 as the corresponding hydrochloride salt.
The hydroxyquinolone and linker component synthesis
began with alkylation of commercially available quinolone 66
with 1,4-bromochlorobutane (67) under basic conditions to
furnish chloroalkoxyquinolone 68. A subsequent alkylation with
hydrochloride salt 65 using potassium carbonate and warm
aqueous ethanol followed by recrystallizative workup resulted
in clean conversion to brexpiprazole (VIII) in 78% yield from
68.
酵素阻害剤
This serotonin-dopamine activity modulator, or SDAM (FW = 433.60 g/mol; CAS 913611-97-9), also known as OPC-34712, Rexulti, 7-{4-[4-(1- benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one, is an atypical antipsychotic drug that acts as a dopamine D2L (Ki = 1.1 nM) and D3 (Ki = 0.3 nM) receptor partial agonist and a partial agonist of 5-HT1A receptors (Ki = 0.12 nM). Brexpiprazole is also an antagonist of the 5-HT2A (Ki = 0.47 nM), 5-HT2B (Ki = 1.9 nM), 5-HT7 (Ki = nM), α1B-adrenergic (Ki = 0.17 nM), α2C-adrenergic (Ki = 0.59 nM), and histamine H1 receptors (Ki = 19 nM). It has negligible affinity for the mACh receptors. Rexulti is an FDA-approved add-on medication for major depressive disorder in adults. See Aripiprazole
Mode of action
Brexpiprazole's suggested mechanism of action is based on its impact on dopamine and serotonin receptors. As a serotonin-dopamine activity modulator (SDAM), it acts as a novel partial agonist for D2 dopamine and serotonin 1A receptors while effectively blocking the serotonin 2A receptors, as well as noradrenergic alpha 1B and 2C receptors.
參考文獻
https://en.wikipedia.org/wiki/Brexpiprazole
https://www.drugbank.ca/drugs/DB09128Maeda, K, et al. "Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator." Journal of Pharmacology & Experimental Therapeutics 350.3(2014):589-604.
Maeda, K, et al. "Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator." Journal of Pharmacology & Experimental Therapeutics 350.3(2014):605.
Yoshimi, N, et al. "Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A receptors. " Pharmacology Biochemistry & Behavior 124(2014):245.
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原材料
準(zhǔn)備製品