Patent Watch

March 31, 2014

Selective 5-HT receptor modulators may deliver focused targeting with fewer side effects. N. I. Carrothers and co-inventors report compounds, represented generally by formula 1, that can modulate serotonin receptors, particularly the 5-HT7 receptor and/or serotonin transporters. (5-HT stands for 5-hydroxytryptamine.) These compounds may be useful for treating disorders that are mediated by serotonin receptor activity.

The neurotransmitter serotonin functions via at least 15 5-HT receptors, 14 of which are expressed in the brain. These receptors are grouped into seven families (5-HT1 through 5-HT7). 5-HT is implicated in the pathogenesis of many diseases, including the central nervous system disorders listed here. Modulating 5-HT receptor activity is an attractive therapeutic target for treating these disorders.

Central nervous system functions and disorders that
may involve 5-HT

Depression
Anxiety
Schizophrenia
Eating disorders
Obsessive-compulsive disorder
Learning dysfunction
Memory dysfunction
Migraine

Chronic pain
Sensory perception
Motor activity
Temperature regulation
Nociception
Sexual behavior
Hormone secretion
Cognition

Many antipsychotic, antidepressant, and antimigraine drugs have nonselective affinities for multiple serotonin receptors and other receptors. Although the lack of selectivity may contribute to favorable therapeutic outcomes, it also can cause undesirable, dose-limiting side effects. For example, tricyclic antidepressants inhibit serotonin, norepinephrine, and 5-HT2 receptors; but they also block histamine H1, muscarinic, and α-adrenergic receptors and can cause such side effects as sedation, blurred vision, and orthostatic hypertension.

Potent serotonin receptor modulators with selective 5-HT receptor affinities are needed to target specific therapeutic mechanisms, improve clinical responses, and decrease side effects. The inventors report the structures of 298 examples of formula 1, including the 5 representative compounds shown in the figure.

General formula and representative examples of selective 5-HT receptor modulators

The inventors used seven binding assays to evaluate the compounds of the invention (see accompanying table). The results of the rat 5-HT7 binding assay are reported as Ki (in μM) for all examples, but only partial results are reported for the other assays. The data for the representative examples are shown in the table.

Example 5-HT7-rat
K(μM)
hSERT
K(μM)
h5-HT6
K(μM)
h5-HT2A
K(μM)
h5-HT2B
K(μM)
h5-HT2C
K(μM)
R5-HT7
K(μM)
2 0.012 0.001 0.047 0.042 0.074 0.76 7.5
3 0.083 0.024 ND 0.225 0.529 1.109 6.9
4 0.023 0.124 ND 0.005 0.012 0.038 7.3
5 0.031 0.224 ND 0.605 7.568 5.00 6.8
6 0.273 ND ND ND ND ND ND
ND = not determined

(Janssen Pharmaceutica, [New Brunswick, NJ]. US Pat. Appl. 20140038943, Feb. 6, 2014; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.