Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

Synthesis and biological evaluation of a new class of multi-target heterocycle piperazine derivatives as potential antipsychotics.

In this study, we designed and synthesized a novel series of multi-receptor ligands as polypharmacological antipsychotic agents by using a multi-receptor affinity strategy. Among them, 3w combines a multi-receptor mechanism with high mixed affinities for D2, 5-HT1A, 5-HT2A and H3 receptors, and low efficacy at the off-target receptors (5-HT2C, H1 and α1 receptor) and human ether-à-go-go-related gene (hERG) channel. In addition, compound 3w exhibits favorable antipsychotic drug-like activities in in vivo assessment. An animal behavioral study revealed that compound 3w significantly reverses apomorphine-induced climbing and MK-801-induced hyperactivity, and avoidance behavior in the CAR test, with a high threshold for catalepsy. Moreover, compound 3w demonstrates memory enhancement in a novel object recognition task and low liabilities for weight gain and hyperprolactinemia in a long-term metabolic adverse effects model. Thus, 3w was selected as an antipsychotic candidate for further development.

Isoquinolinone derivatives as potent CNS multi-receptor D2/5-HT1A/5-HT2A/5-HT6/5-HT7 agents: Synthesis and pharmacological evaluation.

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D2 and serotonin 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors, showed low affinity for off-target receptors (5-HT2C, H1, and α1), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, and DOI-induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia.

Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics.

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics.

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.

Polymorphs and pharmacokinetics of an antipsychotic drug candidate.

A potent antipsychotic drug candidate, 7-(4-(4-(6-fluorobenzo[d]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro -2H-chromen-2-one mesylate(CY611), with good in vitro and in vivo antipsychotic effects was investigated for preformulation evaluation by crystallography methods. Three anhydrous polymorphs(Form I-III), a monohydrate(Form IV), and a NMP solvate(Form V) were discovered and characterized by powder X-ray diffraction, thermal analysis, attenuated total reflection-fourier transform infrared spectroscopy and scanning electron microscopy. Form I, monohydrate Form IV, and a NMP solvate Form V of the drug candidate were isolated, and their structures were determined by single crystal X-ray diffraction. IDR and relative stability experiment were performed. Although Form II has the fastest release rate in water, it easy transformed to monohydrate which has the lowest release rate. In vivo pharmacokinetic study showed that the Form III has the highest bioavailability at 35.4%. Considering the balance between the physicochemical properties, bioavailability and manufacturability of the available polymorphs, Form III may be the optimal form candidate for the eventual formulation.

Polymorphs of DP-VPA Solid Solutions and Their Physicochemical Properties.

Different solid forms possess various physicochemical properties, which can significantly affect the stability, bioavailability, and manufacturability of the final product. DP-VPA, a complex of 1-stearoyl-2-valproyl-sn-glycero-3-phosphatidylcholine (DP-VPA-C18) and 1-palmitoyl-2-valproyl-sn-glycero-3-phosphatidylcholine (DP-VPA-C16), is currently under development as an antiepileptic drug. DP-VPA-C16 and DP-VPA-C18 crystallize together in solid solution forms. The solid forms of DP-VPA solid solution were studied herein. Powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), dynamic vapor sorption (DVS) and optical microscopy were used to characterize the different crystalline forms, known as polymorphs. The physicochemical properties, including hygroscopicity, thermodynamic behavior, and relative stability, of each form were investigated. DVS analysis showed that DP-VPA solid solution reduced the hygroscopicity of DP-VPA-C16. The relative humidity stability study revealed that Forms A and B are relatively stable, while Forms A-1, B-1, C and D are highly unstable under natural humidity. Further analysis revealed that Form A transforms into Form B through milling. Given the physicochemical properties of the available physical forms, Form B may be the optimal form for the formulation and development of antiepileptic drugs.

Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain.

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (µ) opioid receptor agonists, and measured their affinity for σ1 and µ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and µ receptor (Ki µ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/µ receptor profiles, may be a potential candidate for treating neuropathic pain.