Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors

A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1–31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A_2A adenosine receptor (AR) or both hA_2A and hA₁ ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22–31) displayed nanomolar affinity for the hA_2A AR (K_i = 3.62–57 nM) and slightly lower for the hA₁ ARs, thus showing different degrees (3–22 fold) of hA_2A versus hA₁ selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA_2A and hA₁ AR affinities (K_i = 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA_2A AR (K_i = 5.26 nM) and was 22-fold selective versus the hA₁ subtype. Molecular docking investigations performed at the hA_2A AR crystal structure and at a homology model of the hA₁ AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs.     

Structure–activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists

On the basis of potent and selective binding affinity of truncated 4′-thioadenosine derivatives at the human A₃ adenosine receptor (AR), their bioisosteric 4′-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-d-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N⁶ positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A₃ AR. They were less potent than the corresponding 4′-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X = Cl, R = 3-bromobenzyl) showed the highest binding affinity (K_i = 13.0 ± 6.9 nM) at the hA₃ AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4′-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA₃ AR-expressing CHO cells. Although the 4′-oxo series were less potent than the 4′-thio series, this class of human A₃ AR antagonists is also regarded as another good template for the design of A₃ AR antagonists and for further drug development.     

8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A_2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A₁ ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A₁ and A_2AARs at similar concentrations representing dual A₁/A_2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A₁/A_2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, K_i human A₁: 65.5 nM, A_2A: 230 nM; K_i rat A₁: 352 nM, A_2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, K_i human A₁: 642 nM, A_2A: 203 nM; K_i rat A₁: 166 nM, A_2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A₁ and A_2AARs and at MAO-B (K_i human A₁: 393 nM, human A_2A: 595 nM, IC₅₀ human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach.     

Synthesis,molecular modeling and SAR study of novel pyrazolo[5,1-f][1,6]naphthyridines as CB2 receptor antagonists/inverse agonists

Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB₁ and CB₂ receptors. Based on the AgOTf and proline-cocatalyzed multicomponent methodology, the ethyl 5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (12) and ethyl 5-(2,4-dichlorophenyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (13) intermediates were synthesized from the appropriate o-alkynylaldehydes, p-toluenesulfonyl hydrazide and ethyl pyruvate. Most of the novel compounds feature a p-tolyl (8a–i) or a 2,4-dichlorophenyl (8j) motif at the C₅-position of the tricyclic pyrazolo[5,1-f][1,6]naphthyridine scaffold. Structural variation on the carboxamide moiety at the C₂-position includes basic monocyclic, terpenoid and adamantine-based amines. Among these derivatives, compound 8h (N-adamant-1-yl-5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxamide) exhibited the highest CB₂ receptor affinity (K_i = 33 nM) and a high degree of selectivity (K_iCB₁/K_iCB₂ = 173:1), whereas a similar trend in the near nM range was seen for the bornyl analogue (compound 8f, K_i = 53 nM) and the myrtanyl derivative 8j (K_i = 67 nM). Effects of 8h, 8f and 8j on forskolin-stimulated cAMP levels were determined, showing antagonist/inverse agonist properties for such compounds. Docking studies conducted for these derivatives and the reference antagonist/inverse agonist compound 4 (SR144528) disclosed the specific pattern of interactions probably related to the pyrazolo[5,1-f][1,6]naphthyridine scaffold as CB₂ inverse agonists.     

Synthesis and evaluation of new N6-substituted adenosine-5′-N-methylcarboxamides as A3 adenosine receptor agonists

A number of N⁶-substituted adenosine-5′-N-methylcarboxamides were synthesised and their pharmacology, in terms of their receptor affinity, selectivity and cardioprotective effects, were explored. The first series of compounds, 4a–4f and 5a–5f, showed modest receptor affinity for the A₃AR with K_i values in the low to mid μM range. However, the incorporation of a 4-(2-aminoethyl)-2,6-di-tert-butylphenol group in the N⁶-position (in compounds 4g and 5g) significantly improved the affinity with K_i values of 30 and 9 nM, respectively. Improvements in affinity, as well as selectivity were seen when a functionalised linker was introduced. The N⁶-phenyl series, compounds 7a–7d, demonstrated low to mid nanomolar receptor affinities (K_i = 2.3–45.0 nM), with 7b displaying 109-fold selectivity for the A₃AR (vs A₁). The N⁶-benzyl series 9a–9c also proved to be potent and selective A₃AR agonists and the longer chain length linker 13 was tolerated at the A₃AR without abrogation of affinity or selectivity. Cardioprotection was demonstrated by a simulated ischaemia cell culture assay, whereby 7b, 7c, 9a, 9b and 9c all showed cardioprotective effects at 100 nM comparable or better than the benchmark A₃AR agonist IB-MECA, but which were indistinguishable by statistical analysis. For example, compound 9c reduced cell death by 68.0 ± 3.6%.     

Design and synthesis of N6-substituted-4′-thioadenosine-5′-uronamides as potent and selective human A3 adenosine receptor agonists

On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA (N⁶-(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β-d-ribofuranosyl)adenine), which is a potent and selective A₃ adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue (5h) of IB-MECA showed extremely high binding affinity (K_i = 0.25 nM) at the human A₃AR and was more potent than IB-MECA (K_i = 1.4 nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A₃AR binding, although small alkyl analogues were more potent.     

Synthesis and evaluation of N6-substituted apioadenosines as potential adenosine A3 receptor modulators

Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A₃AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of β-d-apio-d-furano- and α-d-apio-l-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N⁶ of β-d-apio-d-furanoadenosine afforded an A₃AR antagonist (10c, K_i = 0.98 μM), while a similar modification of an α-d-apio-l-furanoadenosine gave rise to a partial agonist (11c, K_i = 3.07 μM). The structural basis for this difference was examined by docking to an A₃AR model; the antagonist lacked a crucial interaction with Thr94.     

Design,synthesis and dopamine D4 receptor binding activities of new N-heteroaromatic 5/6-ring Mannich bases

A series of phenylpiperazine-methyl-substituted 1H-pyrrolo[2,3-c]pyridine, imidazo[1,2-c]-, pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidines were prepared as selective dopamine D4-ligands. The pyrrolo[2,3-d]pyrimidine derivatives 12d (K_i = 1,9 nM) and 34d (K_i = 2,4 nM) as well as the pyrrolo[3,2-d]pyrimidine Mannich base 49f (K_i = 2,8 nM) showed high dopamine D4 receptor activity superior to the atypical antipsychotic agent clozapine.     

1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases

Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC₅₀ human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A₁/A_2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, K_i, human receptors, A₁: 0.249 μM, A_2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, K_i A₁: 0.605 μM, K_i A_2A: 0.417 μM, IC₅₀ MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo.     

Pyrrolidine analogs of GZ-793A: Synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2)

Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a–i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [³H]-DTBZ binding (K_i = 560 nM), with 15-fold greater affinity for this site than GZ-793A (K_i = 8.29 μM). Analog 11f also showed similar potency of inhibition of [³H]-DA uptake into vesicles (K_i = 45 nM) compared to that for GZ-793A (K_i = 29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function.     

New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A2A adenosine receptor antagonists

In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A_2A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1–9 and 10–18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties.Compounds 11–16, bearing the amide linker, possessed high affinity and selectivity for the hA_2A AR (K_i = 3.6–11.8 nM). Also derivatives 1–9, featuring an ether linker, preferentially targeted the hA_2A AR but with lower affinity, compared to those of the relative amide compounds. Docking studies, carried out at the hA_2A AR binding site, highlighted some crucial ligand-receptor interactions, particularly those provided by the appended substituent whose nature deeply affected hA_2A AR affinity.     

Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor

Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [³H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (K_i) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (?)-10e (K_i; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (K_i; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (?)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (?)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.     

A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors

A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a K_i of 2 nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays.     

Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives as adenosine receptor antagonists: A preliminary inspection of ligand–receptor recognition process

A new series of triazolotriazines variously substituted at the C5 and N7 (5–25) positions was synthesized and fully characterized at the four adenosine receptor (AR) subtypes. In particular, arylacetyl or arylcarbamoyl moieties were introduced at the N7 position, which enhanced affinity at the hA_2B and hA₃ ARs, respectively, when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compounds with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A_2A AR (range 18.3–96.5 nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA₃ AR (range 311–633 nM) with respect to the unsubstituted derivatives. The binding profiles of the synthesized analogues seemed to correlate with the substitutions at the C5 and N7 positions. At the hA_2B AR, derivative 5, which contained a free amino group at the 7 position, was the most potent (EC₅₀ 3.42 μM) and could represent a starting point for searching new non-xanthine hA_2B AR antagonists. Molecular models of the rA_2A and hA₃ ARs were constructed by homology to the recently reported crystallographic structure of the hA_2A AR. A preliminary receptor-driven structure–activity relationship (SAR) based on the analysis of antagonist docking has been provided.     

Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists

A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines were prepared and their 5-HT₆ receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were evaluated. 3-[(3-Chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC₅₀ = 29.0 nM) and 3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,28} demonstrated the greatest affinity in a 5-HT₆ receptor radioligand binding assay (K_i = 1.7 nM). A screening of 5-HT_2A and 5-HT_2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines are highly selective 5-HT₆ receptor ligands.     

Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A1 and A2A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells

In this work, an enlarged series of 1,2,4-triazolo[4,3-a]pyrazin-3-ones was designed to target the human (h) A_2A adenosine receptor (AR) or both hA₁ and hA_2A ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1–25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (K_i = 7.2 and 10.6 nM) and a complete selectivity for the hA_2A AR were identified. Moreover, several derivatives possessed nanomolar affinity for both hA₁ and hA_2A ARs (both K_i < 20 nM) and different degrees of selectivity versus the hA₃ AR. Two selected compounds (10 and 25) demonstrated ability in preventing β-amyloid peptide (25–35)-induced neurotoxicity in SH-SY5Y cells. Results of docking studies at the hA_2A and hA₁ AR crystal structures helped us to rationalize the observed affinity data and to highlight that the steric hindrance of the substituents at the 2- and 6-position of the bicyclic core affects the binding mode in the receptor cavity.     

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pK_i = 8.4, DA D2 pK_i = 6.0 and hERG fpK_i = 5.2) showed a balanced profile and further refinements are in progress around this molecule.     

Development of novel adenosine receptor ligands based on the 3-amidocoumarin scaffold

With the aim of finding new adenosine receptor (AR) ligands presenting the 3-amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1–8 were evaluated in radioligand binding (A₁, A_2A and A₃) and adenylyl cyclase activity (A_2B) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30-fold selective for the A₃ AR (K_i = 3.24 μM). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A₁, A_2A, and/or A₃ AR ligands. We also performed docking calculations in hA_2A and hA₃ to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates.     

Synthesis and structure–activity relationships of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands

A series of 2-hydrazinyladenosine derivatives was synthesized and investigated in radioligand binding studies for their affinity at the adenosine receptor subtypes with the goal to obtain potent and A_2AAR selective agonists and to explore the structure–activity relationships of this class of compounds at A_2AAR. Modifications included introduction of a second sugar moiety at position 2 of adenosine to form new bis-sugar nucleosides and/or modifications of the 2-position linker in different ways. The performed modifications were found to produce compounds with relatively high A_2AAR affinity and very high selectivity toward A_2AAR. The most potent bis-sugar nucleoside was obtained with the d-galactose derivative 16 which exhibited a K_i value of 329 nM at A_2AAR with marked selectivity against the other AR subtypes. In another set of compounds, compound 3 was modified via replacement of its cyclic structure with mono- and disubstituted phenyl moieties and the resulting hydrazones 10–14 were found to have low nanomolar affinity for A_2AAR. In addition to 3, compounds 10, 11 and 13 have been identified as the most potent compounds in the present series with K_i values of 16.1, 24.4, and 12.0 nM, respectively, at rat A_2AAR. Species differences were tested and found to exist in different rates. Functional properties of the most potent compounds 10, 11, 13 and 16 were assessed showing that the compounds acted as agonists at A_2AAR.     

Discovery of novel α1-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands

The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α_1A-adrenoceptor ligands with K_i values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D₂ receptors. Compound 3i showed almost equal affinity for α_1B- (K_i = 1.9 nM) and α_1D-adrenoceptors (K_i = 2.5 nM) as for α_1A, as well as moderate affinity for 5-HT_1B (K_i = 13 nM) and 5-HT₆ (K_i = 16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands.