Novel spirotetracyclic zwitterionic dual H(1)/5-HT(2A) receptor antagonists for the treatment of sleep disorders.

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Gianotti M, Botta M, Brough S, Carletti R, Castiglioni E, Corti C, Dal-Cin M, Delle Fratte S, Korajac D, Lovric M, Merlo G, Mesic M, Pavone F, Piccoli L, Rast S, Roscic M, Sava A, Smehil M, Stasi L, Togninelli A, Wigglesworth MJ

Novel spirotetracyclic zwitterionic dual H(1)/5-HT(2A) receptor antagonists for the treatment of sleep disorders.

J Med Chem. 2010 Nov 11;53(21):7778-95. doi: 10.1021/jm100856p.

PubMed ID

20942472 [ View in PubMed

]

Abstract

Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Ketotifen	Histamine H1 receptor	Ki (nM)	0.158	N/A	N/A	Details