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.2020 Jul 23;63(14):7529-7544.
doi: 10.1021/acs.jmedchem.9b01953. Epub 2020 Jul 7.

Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties

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Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties

Eric A Wold et al. J Med Chem..

Abstract

Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus,12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.

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Figures

Figure 1.
Figure 1.
Highlighted compounds resulting from the search for synthetic small-molecule 5-HT2CR PAMs. Highlighted here are lead compounds from the published 5-HT2CR PAM drug discovery campaigns. TheC logP, calculated in ChemDraw 18.0, for each compound displays a trend in high lipophilicity.
Figure 2.
Figure 2.
Medicinal chemistry strategy to achieve optimized 5-HT2CR PAMs from PNU-69176E (1). A lincomycin derivative, PNU-69176E (1), was the first synthetic small molecule reported to allosterically modulate 5-HT2CR. Subsequent work has focused on chemical modifications of the PH and the LT to engender drug-like properties.
Figure 3.
Figure 3.
Volume, not length, of the undecyl moiety on PNU-69176E (1) and CYD-1-79 (3) may contribute to 5-HT2CR PAM activity. Compounds 1 and 3 favor similar minimized conformations, which lead to overlapping hydroxyl moieties in the PH and to a folded substructure for the undecyl LT. The preferred, contracted substructure for the undecyl LT suggests that hydrophobic volume is important.
Figure 4.
Figure 4.
Effects of select compounds with shortened LT moieties provide evidence that hydrophobic volume contributes to target engagement. Data are plotted for compounds12 (A),14 (B),35 (C), and37 (D). The effects of these compounds on 5-HT-induced Cai2+ release in h5-HT2CR–CHO cells are shown in the absence (black) and presence of the test compound (red) against the concentration–response curve for 5-HT. The assessment of vehicle (HBSS, blue circle) or vehicle with test compound (green triangle) is also illustrated.
Figure 5.
Figure 5.
Molecular docking illustrates the considerable overlap in ligand poses of six 5-HT2CR PAMs. Six small molecules with a 5-HT2CR PAM profile are represented in different colors along with the endogenous agonist 5-HT. A representative pose for each 5-HT2CR PAM was selected rationally from a top-scoring, enriched cluster docked to the 5-HT2CR X-ray crystal structure (PDB: 6BQG). A measurement from the 5-HT (magenta) indole N atom to the piperidine core N atom of compound 12 was found to be 13.5 Å (illustrated by the dashed line).
Figure 6.
Figure 6.
Docking site surface mapping illustrates the distinct location of the proposed allosteric site in relation to 5-HT bound to 5-HT2CR. (A) Side profile view of 5-HT2CR with the protein surface illustrated around the allosteric docking site in the transmembrane helical bundle. 5-HT (magenta) can be seen below the surface illustration. (B) Docking pose of12 (green) is shown bridging the helical bundle at a site distinct from 5-HT (5-HT2CR PDB: 6BQG).
Figure 7.
Figure 7.
Docking demonstrates that aromatic or aliphatic compact LTs orient toward the hydrophobic pocket between TM2 and TM3 of 5-HT2CR (5-HT2CR PDB: 6BQG). (A) This view features a cutaway of the surface illustration to show how the phenyl and cyclohexyl LTs of 12 (green) and 13 (blue) occupy a hydrophobic pocket within the transmembrane helical bundle. (B) Predicted interactions formed by docking 12 including a possible aromatic interaction with TRP130 in the hydrophobic pocket. (C) Predicted interactions formed by docking 13.
Figure 8.
Figure 8.
Comparison of the allosteric binding site surface map and an independent allosteric binding site prediction program for the 5-HT2CR model (5-HT2CR PDB: 6BQG). (A) Composite model displaying the docking site protein surface and predicted allosteric site volume (magenta balls) seen via cutaway to visualize the overlap between the models. (B) Volume (magenta) determined to be a probable binding pocket capable of accommodating an allosteric modulator. (C) From the same angle as panel B, the docking site protein surface is displayed.
Figure 9.
Figure 9.
Compound12 dose dependently augments the stimulus effects of the selective 5-HT2CR agonist WAY163909. (A) Dose–response relationship for WAY163909 is shown (n = 13 rats). Filled magenta circles denote the rats that chose either the saline- or the WAY163909-associated lever for each condition/dose. Closed black circles denote the mean percentage of rats selecting the WAY163909-associated lever (Y-axis) [*p < 0.05 vs saline (SAL)]. (B) Compound (Cmpd) 12 (0–2 mg/kg) or WAY163909 (0.5 mg/kg) was administered alone or combination as illustrated, with or without pretreatment with SB242084 (0.5 mg/kg). Open bars illustrate the mean percentage of rats selecting the WAY163909-associated lever during combination tests (Y-axis) [*p < 0.05 vs WAY163909 (0.5 mg/kg) alone and ^p < 0.05 vs combination of compound12 plus WAY163909 following pretreatment with SB242084 (0.5 mg/kg). The details of the statistical analyses are found in the Experimental Section.
Scheme 1.
Scheme 1.. Synthesis of CYD-1-79 Analogues with Compact Phenyl or Cyclohexyl LTsa
aReagents and conditions: (a) phenylboronic acid, Pd(PPh3)4, Na2CO3, EtOH/H2O/PhMe = 2:1:1, reflux. (b) H2, PtO2, HCl/MeOH/H2O, rt, and 16 h. (c) (Boc)2O, Et3N, MeOH, rt, and 16 h. (d) LiOH, THF/H2O (v/v = 2:1), rt, and 48 h. (e) amino alcohols, HBTU, DIPEA, DMF, rt, and 16 h. (f) TFA, CH2Cl2, rt.
Scheme 2.
Scheme 2.. Synthesis of CYD-1-79 Analogues with Phenethyl, Ethylcyclohexyl, or Substituted Phenethyl LTsa
aReagents and conditions: (a) phenylacetylenes, CuI, Pd(PPh3)2Cl2, Et3N, rt, and 12 h. (b) H2, PtO2, HCl/MeOH/H2O, rt, and 16 h. (c) (Boc)2O, Et3N, MeOH, rt, and 16 h. (d) LiOH, THF/H2O (v/v = 2:1), rt, and 48 h. (e) Amino alcohols, HBTU, DIPEA, DMF, rt, and 16 h. (f) TFA, CH2Cl2, and rt.
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