KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain.

BACKGROUND: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity. METHODS: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation. RESULTS: Selected results for KM-408: Ki sigma = 7.2*10-8; Ki 5-HT1A = 8.0*10-7; ED50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)-active at 30 mg/kg; SNL (rats, ip)-active at 6 mg/kg; STZ-induced pain (mice, ip)-active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)-active at 30 mg/kg; ED50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)-active at 0.5%; corneal anesthesia (guinea pigs)-active at 0.125%; infiltration anesthesia (guinea pigs)-active at 0.125%. CONCLUSIONS: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment.

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-ß Signaling and Activation of cAMP/PKA Signaling.

Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type ß1 (TGF-ß1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-ß pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.

Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans.

1. Despite the number of favourable properties of lisofylline (LSF), clinical trials on this compound have not yielded the expected results yet. 2. The aims of this study were to evaluate the pharmacokinetics of LSF enantiomers in rats following intravenous, oral and subcutaneous administration of (±)-LSF and to assess the influence of experimental inflammatory disorders, such as multiple organ dysfunction syndrome and severe sepsis on LSF pharmacokinetics. 3. In addition, based on the results obtained an attempt was made to elucidate the possible reasons for the failure of LSF therapy in clinical trials carried out in patients with severe inflammatory disorders. 4. A subcutaneous route of (±)-LSF administration to rats is more favourable than an oral one due to a high bioavailability and a fast absorption of both LSF enantiomers. Pharmacokinetics of LSF in rats is significantly influenced by inflammatory diseases. Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC50 for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time.