Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.     

Discovery of potent and orally active MTP inhibitors as potential anti-obesity agents

We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay.     

Design and synthesis of substituted quinolines as novel and selective melanin concentrating hormone antagonists as anti-obesity agents

A novel series of substituted quinoline analogs were designed and synthesized as potent and selective melanin concentrating hormone (MCH) antagonists. These analogs show potent (nM) activity (12a-k) with a moderate selectivity. Conversely, the conformationally constrained thienopyrimidinone analogs (18a-g) showed improved activity in MCH-1R and selectivity over 5HT2C.     

Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity agents

A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.     

A series of bisaryl imidazolidin-2-ones has shown to be selective and orally active 5-HT2C receptor antagonists

Bisaryl cyclic ureas have been identified as high affinity 5-HT2C receptor antagonists with selectivity over 5-HT2A and 5-HT2B. Compounds such as 8 and 22 have shown oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function in rodents.     

Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence

A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT_2C agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT_2C agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT_2B. Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.     

Tricyclic HIV integrase inhibitors: potent and orally bioavailable C5-aza analogs

A series of C5-aza tricyclic HIV integrase inhibitors was prepared. A highly potent and orally bioavailable compound (compound 9) was identified and selected for development.     

1-[2-[(Heteroaryloxy)heteroaryl]carbamoyl]indolines: novel and selective 5-HT2C receptor inverse agonists with potential as antidepressant/anxiolytic agents

Bisaryl ethers have been identified with excellent 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their potential as novel non-sedating anxiolytic and antidepressants is under investigation.     

7-Sulfonamido-3-benzazepines as potent and selective 5-HT2C receptor agonists: Hit-to-lead optimization

New 7-sulfonamido-3-benzazepines 3 are disclosed as 5-HT_2C receptor agonists. Appropriate substitution of the amino group (R¹R²N–) gave compounds that were potent 5-HT_2C agonists with minimal activation of the 5-HT_2A and 5-HT_2B receptors. Furthermore, representative examples had excellent in vitro ADME properties and good selectivity over ion channel activity.     

Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists

A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.     

1-[2-[(Heteroarylmethoxy)aryl]carbamoyl]indolines are selective and orally active 5-HT2C receptor inverse agonists

Bisarylmethoxyethers have been identified with nanomolar 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 1, 2, 8, 12, 14 and 18 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their therapeutic potential is currently under further investigation.     

Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists

The 5-HT_2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT_2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT_2C is a well validated target for anti-obesity therapy. The synthesis and structure–activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT_2C receptor agonists are presented. Several members of this series were identified as potent 5-HT_2C receptor agonists with high functional selectivity against the 5-HT_2A and 5-HT_2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.     

2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists

The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.     

Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors

This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT_2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure–activity relationship of this series of compounds is presented herein.     

5-HT2A and 5-HT2C receptors and their atypical regulation properties

The 5-HT(2A) and 5-HT(2C) receptors belong to the G-protein-coupled receptor (GPCR) superfamily. GPCRs transduce extracellular signals to the interior of cells through their interaction with G-proteins. The 5-HT(2A) and 5-HT(2C) receptors mediate effects of a large variety of compounds affecting depression, schizophrenia, anxiety, hallucinations, dysthymia, sleep patterns, feeding behaviour and neuro-endocrine functions. Binding of such compounds to either 5-HT(2) receptor subtype induces processes that regulate receptor sensitivity. In contrast to most other receptors, chronic blockade of 5-HT(2A) and 5-HT(2C) receptors leads not to an up- but to a (paradoxical) down-regulation. This review deals with published data involving such non-classical regulation of 5-HT(2A) and 5-HT(2C) receptors obtained from in vivo and in vitro studies. The underlying regulatory processes of the agonist-induced regulation of 5-HT(2A) and 5-HT(2C) receptors, commonly thought to be desensitisation and resensitisation, are discussed. The atypical down-regulation of both 5-HT(2) receptor subtypes by antidepressants, antipsychotics and 5-HT(2) antagonists is reviewed. The possible mechanisms of this paradoxical down-regulation are discussed, and a new hypothesis on possible heterologous regulation of 5-HT(2A) receptors is proposed.     

Substituted hexahydrobenzodipyrans as 5-HT2A/2C receptor probes

A pair of substituted hexahydrobenzodipyrans was designed as molecular probes for determining the steric restrictions of the agonist binding site of serotonin 5-HT2A and 5-HT2C receptors. The rationale for the design of these receptor ligands, their chemical synthesis, rat behavioral pharmacology in the two-lever drug discrimination assay using LSD-trained rats, affinity for cloned rat 5-HT2A and 5-HT2C receptors and agonist functional activities are reported.     

Identification of the binding sites and selectivity of sarpogrelate,a novel 5-HT2 antagonist,to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling

The aim of the present study was to investigate the binding sites interactions and the selectivity of sarpogrelate to human 5-HT(2) receptor family (5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes) using molecular modeling. Rhodopsin (RH) crystal structures were used as template to build structural models of the human serotonin-2A and -2C receptors (5-HT(2A)R, 5-HT(2C)R), whereas for 5-HT(2B)R, we used our previously published three-dimensional (3D) models based on bacteriorhodopsin (BR). Sarpogrelate, a novel 5-HT(2)R antagonist, was docked to the receptors. Molecular dynamics (MD) simulations produced the strongest interaction for 5-HT(2A)R/sarpogrelate complex. Upon binding, sarpogrelate constraints aromatic residues network (Trp(3.28), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2A)R; Phe(3.35), Phe(6.51), Trp(7.40) in 5-HT(2B)R; Trp(3.28), Phe(3.35), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2C)R) in a stacked configuration, preventing activation of the receptor. The models suggest that the structural origin of the selectivity of sarpogrelate to 5-HT(2A)R vs both 5-HT(2B)R and 5-HT(2C)R comes from the following results: (1) The tight interaction between the antagonist and the transmembrane domain (TMD) 3. Asp(3.32) neutralizes the cationic head and interacts simultaneously with carboxylic group hydrogen of the antagonist molecule. (2) Due to steric hindrance, Ser(5.46) (vs Ala(5.46) in 5HT(2B) and 5HT(2C)) prevents sarpogrelate to enter deeply inside the hydrophobic core of the helix bundle and to interact with Pro(5.50). (3) The side chain of Ile(4.56) (vs Ile(4.56) in 5HT(2B)R and Val(4.56) in 5HT(2C)R) constraints sarpogrelate to adjust its position by translating toward the strongly attractive Asp(3.32). These results are in good agreement with binding affinities (pKi) of sarpogrelate for 5-HT(2) receptor family expressed in transfected cell.     

1-Sulfonylindazoles as potent and selective 5-HT6 ligands

As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer’s disease (AD), we have been focused on the 5-HT₆ receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT₆ antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10 mg/kg following an oral administration in rats.     

Potent and orally efficacious benzothiazole amides as TRPV1 antagonists

Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.     

SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist

An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.