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. 2014 Feb 4;5(4):428-33.
doi: 10.1021/ml500005m. eCollection 2014 Apr 10.

3-Amido-3-aryl-piperidines: A Novel Class of Potent, Selective, and Orally Active GlyT1 Inhibitors

Emmanuel Pinard  1 , Daniela Alberati  1 , Ruben Alvarez-Sanchez  1 , Virginie Brom  1 , Serge Burner  1 , Holger Fischer  1 , Nicole Hauser  1 , Sabine Kolczewski  1 , Judith Lengyel  1 , Roland Mory  1 , Christian Saladin  1 , Tanja Schulz-Gasch  1 , Henri Stalder  1
Affiliations

3-Amido-3-aryl-piperidines: A Novel Class of Potent, Selective, and Orally Active GlyT1 Inhibitors

Emmanuel Pinard et al. ACS Med Chem Lett. .

Abstract

3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure-activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration.

Keywords: 3-amido-3-aryl-piperidines; GlyT1 inhibitor; SAR; Schizophrenia.

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Figures

Figure 1
Figure 1
Selection of published GlyT1 inhibitors.
Figure 2
Figure 2
Design principles leading to the identification of active 3-amido-3-aryl-piperidine 8 using pyrrolidino-ethyl-amide 4 as a seed structure.
Scheme 1
Scheme 1. Synthesis of 3-Amido-3-aryl-piperidines 8–43
Reagents and conditions: (a) R2COCl, DIPEA, CH2Cl2, RT, 4–90%; (b) R2CO2H, HATU, DIPEA, DMF, RT, 18–68%; (c) 2- OMe,2′,4-(CF3)2-PhCOCl, DIPEA, CH2Cl2, RT, 86%; (d) HCl, dioxane, RT, 86%; (e) R1I, DIPEA, CH2Cl2, RT, 58%; (f) ketone or aldehyde, NaCNBH3, AcOH, MeOH, RT, 63–89%; (g) acyl- or sulfonyl-chloride, DIPEA, CH2Cl2, RT, 65–99%.
Scheme 2
Scheme 2. Synthesis of N-Methyl-3-amino-3-aryl-piperidines 44a–d
Reagents and conditions: (a) NaN3, TFA, H2O, RT, 87–100%; (b) LiAlH4, THF, RT, 32–63%.
Scheme 3
Scheme 3. Synthesis of N-Methyl-3-amino-piperidines 44f–o and N-Boc-3-amino-3-phenyl-piperidine 45
Reagents and conditions: (a) methyl acrylate, amberlyst A-21, dioxane, RT, 41–85%; (b) cat. Pd2dba3, cat. di-tert-butyl-(2′-methyl-biphenyl-2-yl)-phosphane, Cs2CO3, DME, reflux, 10–90%; (c) MeNH2 (41% in water), CH2O (36% in water), dioxane, RT then 65 °C, 49–94%; (d) zinc, HCl, dioxane, RT, 13–86%; (e) LiAlH4, THF, RT, 71–86%; (f) Lawesson’s reagent, toluene, 80 °C, 77–100%; (g) NaBH4, MeOH, RT, 49–76%; (h) Ra–Ni, H2 (1 atm.), THF, 0 °C, 87–100%; (i) NH4OAc, CH2O (36% in water), EtOH, reflux, 84%; (j) Boc2O, Et3N, CH2Cl2, RT, 70%.
Figure 3
Figure 3
Dose-dependent inhibition of L-687,414-induced hyper-locomotion by 29 in mice. The data represent mean horizontal activity counts per group recorded over a 60 min time period; error bars indicate SEM (n = 8 per group). ##, p < 0.01 versus vehicle (Veh) alone; ***, p < 0.001 versus L-687,414 alone.
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