Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.

Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.

Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.

This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.

A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK1/SERT affinity. Optimization based on NK1/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK1/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Several tetrahydroimidazopyrimidines were prepared using silver assisted cyclization as the key step. The binding affinities of compounds thus prepared were evaluated in vitro toward hCRF1R. Initial lead compound 16 (Ki=32nM) demonstrated modest putative anxiolytic effects in the mouse canopy test. Further optimization using parallel synthesis provided compounds with Ki’s <50nM.

A novel series of [6-chloro-2-trifluoromethyl-7-aryl-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-dialkylamines was discovered as potent CRF(1)R antagonists. The optimization of binding affinity in the series by the parallel reaction approach is discussed herein.

A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4-9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.

A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.

8-Aryl-1,3a,7,8-tetraaza-cyclopenta[a]indenes represent a novel series of high-affinity corticotropin-releasing factor-1 receptor (CRF1R) antagonists. Herein we report the synthesis and SAR around the tricyclic core and the anxiolytic activity of an orally dosed exemplary compound 9d (K(i)=8.0 nM) in a mouse canopy model.

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.