Synthesis and Biological Evaluation of Novel Sigma-1 Receptor Antagonists Based on Pyrimidine Scaffold As Agents for Treating Neuropathic Pain

Abstract

The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.

Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: A critical review

“…Thus, compound 313a may facilitate the development of a novel class drugs for the treatment of neuropathic pain. Further studies of compound 313a and evaluation of these series of derivatives are currently underway in their laboratory and will be reported in due course [106]. In 2016, Cao and co-workers have designed and synthesized a new series of pyridazinone substituted analogues and evaluated for their in vitro antineuropathic pain activity.…”

Investigational sigma-1 receptor antagonists for the treatment of pain

“…Very recently, the group of G. Zhang at the Huazhong University of Science and Technology (China) has reported two interesting series of selective s 1 R antagonists with in vivo activity in different pain models. The quinolinone 14 showed good subtype selectivity and a good dose response behavior in the formalin test in mice [71] and the pyrimidine 15 was even more interesting since, in addition to its good selectivity, it displayed high potency in the formalin test in mice and inhibited thermal hyperalgesia and mechanical allodynia in the neuropathic pain model of chronic constriction of the sciatic nerve in the rat [72]. The efficacy of 14 and 15 was shown to be in the order of that of 32, which, as will be discussed below, is the only s 1 R antagonist being developed in clinical trials for the treatment of pain.…”

Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET)

“…The chemical synthesis of the compounds 13–15 was illustrated in Scheme 1. The 6-hydroxypyridazinone derivatives were prepared following our previously reported work with minor changes28, 29.

Scheme 1Synthesis of 6-hydroxypyridazinone derivatives. Reagents and conditions: (a) maleic anhydride, H 2 O, conc.

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“…Thus, the radioligand with affinity of 0.6‒12 nmol/L could be used for σ 1 R imaging, and range of 0.3‒6 nmol/L will be more suitable. The ex vivo σ 1 R binding affinity of unlabeled HCC0923 (compound 13 ) and HCC0929 (compound 15 ) were measured through previously demonstrated methods (as described in Supporting Information)28, 29. The σ 1 R binding affinities of 13 and 15 were 10.3 and 5.6 nmol/L, with the selectivities of 111.3- and 272.8-fold to σ 2 R, respectively (Table 113, 27).…”