Tetrahydroquinoline derivatives as opioid receptor antagonists

Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58 nM (K_i) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications.     

Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.     

Synthesis and SAR of cis-1-benzoyl-1,2,3,4-tetrahydroquinoline ligands for control of gene expression in ecdysone responsive systems

A library of 35 cis-1-benzoyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolines was prepared. The compounds bore various substitutuents on the benzoyl ring, at the 4-position of the phenylamino ring and at the 6-position of the tetrahydroquinoline ring. The compounds were assayed for their ability to cause expression of a reporter gene downstream of an ecdysone response element in a mammalian cell line engineered to express the ecdysone receptor from Aedes aegypti. In general, compounds with small lipophilic substituents at the meta and para-positions of the benzoyl ring and hydrogen or fluorine at the 4-position of the phenylamino ring and the 6-position of the tetrahydroquinoline ring were the most potent.     

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y_max in the PXR assay for long term preclinical pharmacokinetic (PK) studies.     

Cobaltpolyoxometalate-catalyzed cyclization of glucal with aryl amines: Synthesis of 2,4-disubstituted tetrahydroquinolines

Treatment of 3,4,6-tri-O-acetyl-d-glucal (1) with various aryl amines in the presence of dodecatungstocobaltate under mild and neutral conditions gave sugar derived tetrahydroquinoline derivates.     

Tetrahydroquinolin-3-yl carbamate glucocorticoid receptor agonists with reduced PEPCK activation

Continuing studies on tetrahydroquinoline glucocorticoid receptor anti-inflammatory agents lead to the identification of several tetrahydroquinolin-3-yl carbamates that exhibited steroid-like activity in in vitro transrepression assays with reduced transactivation of phosphoenol pyruvate carboxykinase (PEPCK), a key enzyme in the gluconeogenesis pathway.     

Design and synthesis of new tetrahydroquinolines derivatives as CETP inhibitors

This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.     

Synthesis and in vitro evaluation of 4-substituted furano[3,2-c] tetrahydroquinolines as potential anti-cancer agents

A convenient and mild method for the synthesis of substituted furano [3,2-c]tetrahydroquinoline derivatives was developed, using the multi-component Povarov reaction. Of the synthesized tetrahydroquinoline derivatives, compound 10a displayed the greatest cellular proliferation inhibitory activities with IC₅₀ values of 2.5–16.7?μmol/l. In addition, 10a induced murine C6 glioma cell apoptosis in a dose-dependent manner by up-regulating the expression of Bax, caspase-3, and caspase-9, and by down-regulating Bcl-2. Our findings suggest that these novel compounds have potential as therapeutic agents via inducing mitochondrial apoptosis.     

Structure–activity relationship (SAR) investigations of tetrahydroquinolines as BKCa agonists

The membrane bound large-conductance, calcium-activated potassium channel (BKCa) is an important regulator of neuronal activity. Here we describe the identification and structure–activity relationship of a novel class of potent tetrahydroquinoline BKCa agonists. An example from this class of BKCa agonists was shown to depress the spontaneous neuronal discharges in an electrophysiological model of migraine.     

Synthesis and characterization of 5,6,7,8-tetrahydroquinoline C5a receptor antagonists

A novel series of substituted 2-aryl-5-amino-5,6,7,8-tetrahydroquinoline C5a receptor antagonists is reported. Synthetic routes were developed that allow the substituents on the tetrahydroquinoline core to be efficiently varied, facilitating determination of structure-activity relationships. Members of the series display high binding affinity for the C5a receptor and are potent functional antagonists.     

Design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors

Gamma-secretase is a key enzyme involved in the production of beta-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of gamma-secretase has been an attractive approach to AD therapy. In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described.     

Synthesis and SAR of novel histamine H3 receptor antagonists

The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H(3) receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H(3) receptors are reported.     

Synthesis and stereochemical investigations of novel nitrogen-containing 13alpha-estrone derivatives

Novel tetrahydroquinoline 11 and N-aryl d-homo derivatives 12 in the 13alpha-estrone series were synthesized effectively, starting from the secoaldehyde 8 and mono- or disubstituted anilines 9. The chemoselectivity of the cyclization reactions depended upon the nature of the substituents in the anilines. All transformations proceeded in a highly stereoselective manner, yielding only one diastereomer. Condensed 11 and d-homo derivatives 12 both have the usual ring C chair conformation in the solid state.     

Design and optimization of aniline-substituted tetrahydroquinoline C5a receptor antagonists

A series of aniline-substituted tetrahydroquinoline C5a receptor antagonists were discovered. A functionality requirement of ortho substitution on the aniline was revealed. Secondary anilines, in general, outperformed tertiary analogs in inhibition of C5a-induced calcium mobilization. Further enhancement of activity was realized in the presence of an ortho hydroxyalkyl side chain. The functional IC₅₀ of selected analogs was optimized to the single-digit nanomolar level.     

Tetrahydroquinoline glucocorticoid receptor agonists: discovery of a 3-hydroxyl for improving receptor selectivity

We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists.     

Synthesis and dopaminergic activity of heterocyclic analogues of 5,6-dihydroxy-2-aminotetralins

The heterocyclic analogues of 5,6-dihydroxy-2-aminotetralins (6) were synthesized and their in vitro dopaminergic activity was compared to that of (-)-DP-5,6-ADTN and the novel potent agonist Z12571. The results show that changing the cathecol ring for a heterocycle decreases the D1-like activity of the target molecules 6. However, the D2-like activity of tetrahydroquinoline (6j) was comparable to that of (-)-DP-5,6-ADTN.     

Stereoselectivity in reactions of amino acids catalyzed by pyridoxal derivatives carrying rigidly-attached chirally-mounted basic groups--transamination,racemization, decarboxylation,retro-aldol reaction,and aldol condensation

A tetrahydroquinoline ring was used to mount the critical functional groups of pyridoxal, and also two examples of rigidly held chirally mounted basic groups. They were able to selectively catalyze decarboxylation, aldol reaction, and retro-aldol reaction of amino acids rather than transamination, and with stereoselectivity. In the aldol reaction of glycine with acetaldehyde to synthesize threonine and allo-threonine, one of the catalysts reversed its stereoselectivity when the basic group was protonated. The observed stereoselectivities were all consistent with prediction.     

Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain

Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.     

Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.     

Identification of a Tetrahydroquinoline Analog as a Pharmacological Inhibitor of the cAMP-binding Protein Epac

The cAMP-binding protein Epac is a therapeutic target for the treatment of various diseases such as cardiac hypertrophy and tumor invasion. This points out the importance to develop Epac inhibitors to better understand the involvement of these cAMP sensors in physiology and pathophysiology. Here, we have developed a functional fluorescence-based high-throughput assay with a Z′ value around 0.7 for screening Epac-specific antagonists. We identified an Epac1 inhibitor compound named CE3F4 that blocked Epac1 guanine nucleotide exchange activity toward its effector Rap1 both in cell-free systems and in intact cells. CE3F4 is a tetrahydroquinoline analog that fails to influence protein kinase A holoenzyme activity. CE3F4 inhibited neither the interaction of Rap1 with Epac1 nor directly the GDP exchange on Rap1. The kinetics of inhibition by CE3F4 indicated that this compound did not compete for binding of agonists to Epac1 and suggested an uncompetitive inhibition mechanism with respect to Epac1 agonists. A structure-activity study showed that the formyl group on position 1 and the bromine atom on position 5 of the tetrahydroquinoline skeleton were important for CE3F4 to exert its inhibitory activity. Finally, CE3F4 inhibited Rap1 activation in living cultured cells, following Epac activation by either 8-(4-chlorophenylthio)-2′-O-methyl-cAMP, an Epac-selective agonist, or isoprenaline, a non-selective β-adrenergic receptor agonist. Our study shows that CE3F4 and related compounds may serve as a basis for the development of new therapeutic drugs.