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Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.

Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

[Image: see text] GSK2798745, an antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently investigated in clinical trials for the treatment of cardiac and respiratory diseases. Human plasma and urine samples collected from healthy volunteers following oral administration were analyzed to identify circulating and excreted metabolites of the parent drug. One major circulating metabolite (1) was found in pooled human plasma samples, accounting for approximately half of the observed drug-related material. Isolation of metabolite 1 from urine samples followed by MS and NMR studies led to a putative structural assignment of 1 where hydroxylation of GSK2798745 occurred on the central ring, producing a penta-substituted cyclohexane structure containing three stereocenters. Two unique chemical syntheses of the proposed structure were developed to confirm the identity of metabolite 1 and provide access to gram quantities for biological characterization.

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.

Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopping approach, which relied on use of an internal H-bond to replace a saturated heterocyclic ring. Optimization of the lead through investigation of both aryl regions revealed approaches to increase potency through substituents believed to enhance separate intramolecular and intermolecular H-bond interactions. A proposed internal H-bond between the amine and neighboring benzenesulfonamide was stabilized by electronically modulating the benzenesulfonamide. In the aryl ether moiety, substituents para to the nitrile demonstrated an electronic effect on TRPV4 recognition. Finally, the acyclic amines inactivated CYP3A4 and this liability was addressed by modifications that sterically preclude formation of a putative metabolic intermediate complex to deliver advanced TRPV4 antagonists as leads for discovery of novel medicines.

Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative—and potentially superior—therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

A series of novel [3a,4]dihydropyrazolo[1,5a]pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kβ. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R3) and back-pocket (R4) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey.

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.

Further optimization of the biaryl amide series via extensively exploring structure–activity relationships resulted in potent and subtype selective M1 agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure–activity relationships, subtype selectivity for M1 over M2–5, and DMPK properties of these novel compounds are described.

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.

A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure–activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.

A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.

High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.

SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as 1a with a Ki of 4 nM. The synthesis and structure–activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.

A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.

High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.

A protocol for monoacylation of unprotected symmetrical diamines with a resin-bound benzoic acid is described. The nature of the resin (gel-based polystyrene vs highly crosslinked macroporous polystyrene) was found to play a minor role in acylation selectivity. Rather, the concentration of the diamine dictates the ratio of mono- and diacylated products. Thus, by employing a high concentration of symmetrical diamine (e.g., 1 M, 20 equiv), monoacylation can be selectively achieved for a variety of unprotected symmetrical alkyl and aryl diamines.

The use of a multiplex mimetic assay led us to identify 1,4-dihydropyrimidines with potent and selective calcitonin receptor mimetic activity. Subsequent modification of the dihydropyrimidine scaffold led to a series of molecules that were efficacious in a neonatal mouse calvaria in vitro model. Dihydropyrimidine 5h, in particular, was identified as a calcitonin mimetic (EC50=6 μM), active in-vivo in the Weanling rat model when administered subcutaneously.

A robust ‘catch and release’ synthesis of fused 2-alkylthio-3-substituted-pyrimidinones mediated by the polymer-bound base P-BEMP is described. This reengineered synthesis combines the efficiency of the classical synthesis (three steps, three diversity points) with the practical benefits of resin-bound reagents. The solution-phase strategy, reagent compatibility, and the results of a representative 48-member combinatorial library are described and presented herein.

The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on 125 I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC 50 . When delivered intraperitoneally, compounds 3a , 3b , and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.

The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the aryl fluoride with either an alpha- or beta-substituted beta-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is accomplished in the presence of SnCl(2).H(2)O. Hydrolysis of the ester is carried out in the presence of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the benzodiazepinone is accomplished with alkyl halides in the presence of K(2)CO(3) in acetone. The desired products are cleaved from solid supports and obtained in 46-98% isolated yields.

The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.

Farbige Glasperlen und Deckel ergeben eine einfache Farbcodierungsmethode und ermoglichen eine leichte Identifikation der individuellen Bestandteile von kombinatorischen Bibliotheken.

The preparation of 1-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 7 is described. The cyclization of a resin bound o -phenylenediamine 4 with thiocarbonyldiimidazole (TCD) in THF provided a benzimidazole-2-thione 5 . Treatment of 5 with benzylic halides in the presence of DIEA resulted in the resin bound 1-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 6 . The final products were cleaved from the resin and obtained in from 74% to 99% yields.

The preparation of 14-membered macrocycles from a resin-bound orthogonally protected lysine residue is described. Reductive alkylation of the a-nitrogen followed by acylation with an Fmoc-aminoacid provides a protected dipeptide precursor. Removal of the Fmoc-group, acylation with a succinic anhydride, methyltrityl-group removal and macrocyclization provides the desired macrocycles, after TFA cleavage, in excellent yield and purity.

A procedure for preparing substituted aminosulfonyl ureas on solid support is described. Chemoselective reaction of chlorosulfonyl isocyanate with the Wang resin followed by reaction with an amine provides resin-bound substituted aminosulfonylcarbamates. Heating of the resultant resin in THF with a second amine provides the desired substituted aminosulfonyl ureas in good yield and purity. © 1997 Elsevier Science Ltd.

The solid phase synthesis of 3,4-disubstituted-7-carbamoyl-1,2,3,4-tetrahydroquinoxalin-2-ones 8 is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the resin-bound aryl fluoride with an α-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group with SnCl2·H2O and subsequent intramolecular cyclization result in the formation of the core quinoxalinone. Selective alkylation at the N-4 position of the quinoxalinone is accomplished with alkyl halides in the presence of K2CO3. The desired products are cleaved from solid supports and obtained in from 32 to 93% isolated yields.

The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

Screening of our sample collection for novel structures with endothelin receptor (ET A and ET B ) binding affinity, resulted in the discovery of structure I (R = H). This unique bicyclic diacid elicited modest affinity for both cloned human receptors (0.8 μM, ET A and 7.9 μM, ET B ). Substitution at ‘R’ resulted in increased affinity for both receptors.

Non-peptide ligands for peptide receptors for the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells transfected with the rat AT1 receptor a prototype of these compounds, L-162,313 stimulated phosphoinositide hydrolysis with an EC50 of 33 +/- 11 nM. The maximal response to the compound was 50% of that of angiotensin II in COS-7 cells but only 3% in stably transfected Chinese hamster ovary cells. The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells. In Chinese hamster ovary cells, L-162,313 also acted as an insurmountable antagonist of the angiotensin stimulated phosphoinositide hydrolysis. In contrast to previously tested non-peptide ligands, L-162,313 bound with reasonably high affinity to the Xenopus laevis AT1 receptor. In the human receptor, the binding of L-162,313 was found to be unaffected by point mutations in transmembrane segments III and VII, which impaired the binding of biphenylimidazole antagonists. Substitutions in the extracellular domains of the human and rat receptor, which impaired the binding of angiotensin II, did not affect the binding of L-162,313. It is concluded that a subset of biphenylimidazole compounds can act as high affinity partial agonists on the AT1 receptor. These compounds have molecular interactions with the receptor which appear to differ both from that of the structurally similar non-peptide antagonists and from that of their functional counterpart, the peptide agonist.

A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors has been identified. This chemotype has provided an excellent tool compound, 18, that showed potent growth inhibition in the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage-independent conditions, and it also demonstrated pharmacodynamic effects and efficacy in a PTEN-deficient prostate cancer PC-3 xenograft mouse model.

A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (∼ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line.

A series of subnanomolar (IC50 triazolinone-based AT1/AT2-balanced AII antagonists has been identified. The 70-240-fold gain in AT2 activity relative to prototype compounds was achieved by the introduction of a 5-acylamino group on the N2-aryl moiety and the addition of (3-F-5'-Pr)biphenyl substituents on 4. These analogues exhibited AT2/AT1 IC50 rations of ≤1 in multiple assay systems including human adrenal.

Inspired by the modest success of a phenoxyphenylacetic acid ( I ) biphenyl tetrazole replacement, 1,3-benzodioxole-2-carboxylates and 1,3-benzodithiole-2-carboxylates ( II ) and their respective tetrazole analogs ( III ) were investigated as AII antagonists. These compounds, essentially conformationally restricted analogs of the phenoxyphenylacetic acid series, proved to be quite potent in vitro .

A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.

The biphenyl fragment of the potent angiotensin II receptor antagonist L-158,809 was replaced by a phenylthiophene and a phenylfuran moiety. Replacement of the tetrazole-bearing phenyl by a thiophene resulted in a small loss in binding affinity (

Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared. Radiolabeled Losartan (DuP 753)1,2, L-158,641 (EXP3174)3 and L-158,8094,5 were prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl. Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl

A reasonably concise, stereochemically linear total synthesis of breynolide has been achieved. Importantly, the three secondary hydroxyl groups in penultimate intermediate 22 are differentially protected; this substance therefore holds considerable promise as a precursor to the biologically active glycosides

The total synthesis of (±)-breynolide (3), an aglycon derivative of the potent, orally active hypocholesterolemic glycoside breynin A, has been achieved via a stereochemically linear strategy. The successful approach entailed union of the anion derived from 58 with aldehyde 54 followed by an anomerically driven spiroketalization-equilibration protocol

The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.

The preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Varia- tions of the ring size of the azacycle and substitution on the pyridine had dramatic eAects on receptor binding aAnity with IC50 sa t the a4b2 nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidi- nyl)oxy)pyridine 27f with an IC50 of 22 nM. # 2000 Elsevier Science Ltd. All rights reserved. The discovery of compounds that can safely treat both acute and chronic pain without the side eAect of drug dependency would be an important advance in pain management. The discovery of epibatidine 1, a nAChR modulator, suggested that it might be possible to obtain an analgesic compound that is devoid of opioid-related side eAects. 1 But the narrow therapeutic index of epiba- tidine prohibited further development of the compound as an analgesic. 2 The discovery of ABT-594 fueled fur- ther investigation of the therapeutic potential of ligands that bind to the nAChR. 3 ABT-594 was shown to be at least 20 times more potent than morphine as an analgesic. 3a Furthermore, the initial findings suggested that the compound did not elicit the drug dependency associated with morphine. To this end, we now report the discovery of novel pyridyl ethers as potent ligands for the a4b2 nAChR subtype. Our program focused on using natural product ligands such as epibatidine 1 and nicotine 2 as starting points for analogue design as shown in Figure 1. We retained the pyridyl group as a part of the novel ligands. The only criteria left on the molecule was to place nitrogen in an optimal distance from the 3 position of the pyridine. Numerous models have been suggested in the literature regarding the location and angle of the nitrogen in respect to the pyridine. 4 As part of our structure-activity program, we identified the pyridyl ethers 3 as potent ligands that bound to the a4b2 nAChR subtype.