Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness

Bioorg Med Chem Lett. 2014 May 15;24(10):2236-9. doi: 10.1016/j.bmcl.2014.03.098. Epub 2014 Apr 8.

Abstract

Several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H3R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H3R (pKi (hH3R)=9.3) clogS, clogP, LE, LipE, and LELP values of -2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pKi (hH3R)=8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively.

Keywords: Antagonists; Drug-likeness; GPCR; Histamine H(3) receptor; Lipophilicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Histamine Antagonists / chemical synthesis
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacology*
  • Humans
  • Kinetics
  • Ligands
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Protein Binding
  • Receptors, Histamine H3 / chemistry
  • Receptors, Histamine H3 / metabolism*

Substances

  • Histamine Antagonists
  • Ligands
  • Piperidines
  • Receptors, Histamine H3
  • 1-benzylpiperidine