Synthesis and Evaluation of Novel Α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain

molecules Article Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain Haotian Li, Shiyong Fan, Jingchao Cheng, Ping Zhang, Bohua Zhong * and Weiguo Shi * Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; [email protected] (H.L.); [email protected] (S.F.); [email protected] (J.C.); [email protected] (P.Z.) * Correspondence: [email protected] (B.Z.); [email protected] (W.S.); Tel.: +86-10-669-316-39 (B.Z.); +86-10-668-746-12 (W.S.) Academic Editor: Diego Muñoz-Torrero Received: 28 April 2016; Accepted: 14 June 2016; Published: 23 June 2016 Abstract: The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted. Keywords: neuropathic pain; α-aminoamide derivatives; voltage-gated sodium channel blockers 1. Introduction Neuropathic pain is a chronic disease caused by lesion or dysfunction of the somatosensory system [1,2]. As a result, neuropathic pain reduces the quality of life of afflicted patients and increases the cost of their medical care. Currently, there is a lack of specific analgesics to treat this clinical problem [3,4]. Recent studies have suggested that voltage-gated sodium channels (VGSCs) may be an ideal therapeutic target for neuropathic pain. Some α-aminoamide derivatives, including ralfinamide (Figure1), are potential anti-neuropathic drug candidates. Ralfinamide is an orally active selective blocker of the VGSC, Nav1.7, and has been developed by Newron Pharmaceuticals [5]. Data from animal models of inflammatory and neuropathic pain have suggested that ralfinamide exhibits a significant analgesic effect while also having a well-tolerated safety profile [6–8]. Moreover, ralfinamide is the only small molecule drug in a late-stage clinical trial for the treatment of neuropathic pain [9–13]. However, the anti-allodynic efficacy and Nav1.7-selectivity of ralfinamide need further improvement. Safinamide (Figure1), another α-aminoamide derivative, has been approved by the European Commission in February 2015 for the treatment of Parkinson’s disease. In contrast with the activity of ralfinamide, safinamide exhibits selective and reversible monoamine oxidase B (MAO-B) inhibitory activity [14–16]. The only structural difference between ralfinamide and safinamide is the position of the fluoro substituent (Figure1). Such slight chemical structural differences between ralfinamide and safinamide result in dramatic changes in pharmacological activity, indicating that delicate structure-activity relationship (SAR) inspection is needed for these types of compounds. Molecules 2016, 21, 793; doi:10.3390/molecules21070793 www.mdpi.com/journal/molecules Molecules 2016, 21, 793 2 of 8 Molecules 2016, 21, 793 2 of 8 Molecules 2016, 21, 793 2 of 8 FigureFigure 1.1. Chemical structures ofof ralfinamideralfinamide andand safinamide.safinamide Figure 1. Chemical structures of ralfinamide and safinamide Here, a set of novel compounds that contain an indole ring and the α-aminoamide pharmacophore Here, a set of novel compounds that contain an indole ring and the α-aminoamide pharmacophore Here, a set of novel compounds that contain an indole ring and the α-aminoamide pharmacophore+ were designed (Figure 2). According to recent studies, indole derivatives can also exhibit Na+ channel were designed (Figure2 2).). AccordingAccording toto recent recent studies, studies, indole indole derivatives derivatives can can also also exhibit exhibit Na Na+ channel inhibitory activity [17]. Therefore, we replaced the A ring of ralfinamide with an indole ring and inhibitory activity [17]. [17]. Therefore, Therefore, we we replaced replaced the the A A ring of ralfinamide ralfinamide with an indole ring and varied the substitution position of the indole ring and the pharmacophore (Figure 2). Meanwhile, the varied the substitution position of the indole ring and the pharmacophore (Figure2 2).). Meanwhile,Meanwhile, thethe position of the oxygen atom between the A ring and B ring was different to that of ralfinamide, which position of the oxygen atom between the A ring and B ring was different to that of ralfinamide,ralfinamide, which plays a critical role in the inhibitory activity and specific target selectivity based on our previous plays aa criticalcritical role role in in the the inhibitory inhibitory activity activity and and specific specific target target selectivity selectivity based based on our on previous our previous study. study. The bioactivity of the resulting compounds for treating neuropathic pain were subsequently Thestudy. bioactivity The bioactivity of the resulting of the resulting compounds compounds for treating for neuropathictreating neuropathic pain were pain subsequently were subsequently evaluated evaluated and compared in this paper. andevaluated compared and compared in this paper. in this paper. CH3 CH3 4' NH2 4' N (S) NH2 2 B NH (S) F 2 B H O 3F O O 3 A O A Ralfinamide: 2-F Ralfinamide:Safinamide: 3-F2-F Safinamide: 3-F Pharmacophore Pharmacophore 4' CH3 4' CH3 4 B NH2 4 O B N (S) NH HN O 3' NH 2 HN A 5 (S)O A 5 3' H O 7 6 7 6 Figure 2. The design of novel α-aminoamide derivatives. Substitutions were made in the A ring at Figure 2. The design of novel α-aminoamide derivatives. Substitutions were made in the A ring at Figurepositions 2. The4, 5, design6 or 7. Substitutions of novel α-aminoamide involving the derivatives. α-aminoamide Substitutions pharmacophore were made were in made the A in ring the atB positions 4, 5, 6 or 7. Substitutions involving the α-aminoamide pharmacophore were made in the B positionsring at either 4, 5, the 6 or 3’ 7.or Substitutions4’ position. involving the α-aminoamide pharmacophore were made in the Bring ring at ateither either the the 3’ 3’or or 4’ 4’position. position. 2. Results and Discussion 2. Results Results and and Discussion Discussion 2.1. Synthesis 2.1. Synthesis As shown in Scheme 1, target compounds 6a–d and 7a–d were synthesized in four steps. First, As shown in Scheme 1, target compounds 6a–d and 7a–d were synthesized in four steps. First, the aldehydeAs shown group in Scheme of terephthalaldehyde1, target compounds (1a) or 6aisophthalaldehyde–d and 7a–d were (1b synthesized) was reduced in by four sodium steps. First,the aldehyde the aldehyde group groupof terephthalaldehyde of terephthalaldehyde (1a) or (isophthalaldehyde1a) or isophthalaldehyde (1b) was (1b reduced) was reducedby sodium by borohydride, then brominated with NBS using PPh3 as a catalyst to obtain the intermediate 3a and 3b, borohydride, then brominated with NBS using PPh3 as a catalyst to obtain the intermediate 3a and 3b, sodiumrespectively. borohydride, Next, 3a and then 3b brominated were etherified with with NBS hydroxyindoles using PPh3 as by acatalyst Williamson to obtain ether synthesis. the intermediate Finally, respectively. Next, 3a and 3b were etherified with hydroxyindoles by Williamson ether synthesis. Finally, 3a4a–andd and3b 5a, respectively.–d were converted Next, 3aintoand a series3b were of α etherified-aminoamide with derivatives hydroxyindoles by reductive by Williamson amination. ether synthesis.4a–d and 5a Finally,–d were4a converted–d and 5a into–d awere series converted of α-aminoamide into a series derivatives of α-aminoamide by reductive derivatives amination. by reductive amination. Molecules 2016, 21, 793 3 of 8 Molecules 2016, 21, 793 3 of 8 Molecules 2016, 21, 793 3 of 8 Scheme 1. Synthesis of compounds 6a–d and 7a–d. Reagents and Conditions: (i) NaBH4, C2H5OH, THF, Scheme 1. Synthesis of compounds 6a–d and 7a–d. Reagents and Conditions: (i) NaBH4,C2H5OH, THF, ice-bath, 6 h; (ii) NBS, PPh3, DCM, 4.5 h; (iii) K2CO3, KI, acetone, 58 °C,˝ 24 h; (iv) Cs2CO3, DMF, 40 °C, ˝ ice-bath, 6 h; (ii) NBS, PPh3, DCM, 4.5 h; (iii) K2CO3, KI, acetone, 58 C, 24 h; (iv) Cs2CO3, DMF, 40 C, overnight; (v) L-alaninamide hydrochloride, NaBH3CN, MeOH, 8 h. overnight; (v) L-alaninamide hydrochloride, NaBH3CN, MeOH, 8 h. 2.2. AnalgesicScheme Activity 1. Synthesis of Target of compounds Compounds 6a–d andin Formalin 7a–d. Reagents Test and Conditions: (i) NaBH4, C2H5OH, THF, 2.2. Analgesicice-bath, Activity 6 h; (ii) of TargetNBS, PPh Compounds3, DCM, 4.5 h;in (iii) Formalin K2CO3, KI, Test acetone, 58 °C, 24 h; (iv) Cs2CO3, DMF, 40 °C, Weovernight; firstly (v)screened L-alaninamide the in hydrochloride, vivo activities NaBH of3 CN,the MeOH,compounds 8 h. in mice using a formalin test, Webecause firstly our screened studies have the in suggested vivo activities this type of of the compounds compounds with in micethe oxygen using atom a formalin at this test,position because our studiesexhibited2.2. Analgesic have lower suggested Activity in vitro of Nav1.7 Target this type Compounds inhibitory of compounds inactivity Formalin th an withTest that the of oxygenralfinamide, atom so atthe this inhibitory position activity exhibited loweragainstin vitroWe Nav1.7 Nav1.7firstly was screened inhibitory not sufficient the in activity vivofor showingactivities than that theirof the of re ralfinamide,alcompounds analgesic efficiency.inso mice the using inhibitory We testeda formalin the activity effecttest, againstof the compounds at a single dosage of 10 mg/kg, according to the effective doses resulting in a 50% Nav1.7because was not our sufficient studies have for suggested showing this their type realof compounds analgesic with efficiency.

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