Novel and highly potent histamine H3 receptor ligands. Part 3: An alcohol function to improve the pharmacokinetic profile

Labeeuw, Olivier; Levoin, Nicolas; Poupardin-Olivier, Olivia; Calmels, Thierry; Ligneau, Xavier; Berrebi-Bertrand, Isabelle; Robert, Philippe; Lecomte, Jeanne‐Marie; Schwartz, Jean‐Charles; Capet, Marc

doi:10.1016/j.bmcl.2013.02.118

Cited by 5 publications

(1 citation statement)

References 22 publications

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“…In this regard, many series of compounds with great structural diversity have been synthesized [ 6 ]. However, there is a common pharmacophore consisting of a basic moiety, separated by a linker (often saturated alkyl chains) from an aromatic zone attached to an arbitrary scaffold that is generally hydrophobic [ 7 ]. First generation H 3 R ligands usually contain imidazole-based scaffolds, with regard to histamine structure [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Substituted Purines as High-Affinity Histamine H3 Receptor Ligands

et al. 2022

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Continuing with our program to obtain new histamine H3 receptor (H3R) ligands, in this work we present the synthesis, H3R affinity and in silico studies of a series of eight new synthetically accessible purine derivatives. These compounds are designed from the isosteric replacement of the scaffold presented in our previous ligand, pyrrolo[2,3-d]pyrimidine ring, by a purine core. This design also considers maintaining the fragment of bipiperidine at C-4 and aromatic rings with electron-withdrawing groups at N-9, as these fragments are part of the proposed pharmacophore. The in vitro screening results show that two purine derivatives, 3d and 3h, elicit high affinities to the H3R (Ki values of 2.91 and 5.51 nM, respectively). Both compounds are more potent than the reference drug pitolisant (Ki 6.09 nM) and show low toxicity with in vitro models (IC50 > 30 µM on HEK-293, SH-SY5Y and HepG2 cell lines). Subsequently, binding modes of these ligands are obtained using a model of H3R by docking and molecular dynamics studies, thus determining the importance of the purine ring in enhancing affinity due to the hydrogen bonding of Tyr374 to the N-7 of this heterocycle. Finally, in silico ADME properties are predicted, which indicate a promising future for these molecules in terms of their physical–chemical properties, absorption, oral bioavailability and penetration in the CNS.

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Section: Introductionmentioning

confidence: 99%