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Analgesic and antipruritic pharmaceutical composition and application method thereof

A composition and drug technology, applied in the field of medicinal chemistry, can solve problems such as unclear, poor effect, and poor analgesic effect

Active Publication Date: 2022-02-22
上海瑞虎康医药合伙企业(有限合伙)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] PF-05089771 inhibits human Na v 1.7 ICs 50 The value is 11nM, but it failed due to poor effect in clinical research for the treatment of diabetic neuropathic pain (A.McDonnell.,Efficacy of the Nav1.7blocker PF-05089771in a randomised,placebo-controlled,double-blind clinical study subjects with painful diabetic peripheral neuropathy.Pain.2018Aug;159(8):1465-1476.), the reason for its poor analgesic effect in vivo is not clear

Method used

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  • Analgesic and antipruritic pharmaceutical composition and application method thereof
  • Analgesic and antipruritic pharmaceutical composition and application method thereof
  • Analgesic and antipruritic pharmaceutical composition and application method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example of the effect of giving a single drug

[0035] To test Na v 1.7 and Na v 1.8 The effect of inhibitors on relieving neuropathic pain induced by peripheral nerve injury at different time points. We purchased 5-6 week-old C57 / BJ6 mice (Shanghai Slack Experimental Animal Co., Ltd.), and fed them for 6 months. The mouse was placed in a transparent plexiglass cover on an iron frame, and the basic mechanical threshold (paw withdrawal threshold, PWT) of the mouse was detected with Von Frey (DanMicGlobal, CA, USA) after 30 minutes. The average threshold is 1.54g ± 0.07g, see figure 1 . The neuropathic pain C57 / BJ6 mouse model of Spared nerve injury (SNI) nerve injury was prepared according to the references, and the mechanical pain threshold of the mice was also detected by VonFrey at 2 weeks, 4 weeks, and 6 weeks after the operation, and the threshold value was significantly Below the preoperative threshold, the average thresholds were 0.14g±0.02g, 0.06g±0.01g, 0.12...

Embodiment 3

[0045] In order to find the best analgesic Na v 1.7 and Na v 1.8 combinations of inhibitor classes, we tested another Na v 1.7 The analgesic effect of the combination of inhibitors GNE-0439 and PF-04885614. After intraperitoneal injection of 20 μg / kg GNE-0439 and 90 μg / kg PF-04885614 into mice 6 weeks after SNI, Von Frey was used to detect the mechanical threshold of the mice one hour later, and it was found that the combination of GNE-0439 and PF-04885614 obtained the sedation The analgesic effect was not significantly better than the analgesic effect of GNE-0439 alone (△PWT=0.77g±0.14g, see Figure 9 ), and the analgesic effect (△PWT=1.38g±0.15g) was not as good as the combined administration of 2mg / kg PF-05089771 and 90μg / kg PF-04885614. Then we tested another Na v1.8 Analgesic effect of combined use of inhibitors PF-04531083 and PF-05089771. After intraperitoneal injection of 2mg / kg PF-05089771 and 10mg / kg PF-04531083 to mice 6 weeks after SNI, the mechanical threshol...

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Abstract

The invention discloses an analgesic and antipruritic pharmaceutical composition and an application method thereof, and belongs to the technical field of medical chemistry. The research of the invention finds that the analgesic effect generated by independently inhibiting the activity of Nav1.7 or Nav1.8 is reduced along with the time history of peripheral nerve injury, and also finds that a neuropathic pain mouse with poor response to the Nav1.7 small-molecule inhibitor has better response to the Nav1.8 small-molecule inhibitor. According to the discovery, the analgesic effect of combined administration of different Nav1.7 inhibitors and Nav1.8 inhibitors is researched, and it is found that the analgesic effect can be remarkably improved and the response rate can be increased to 100% by combined administration of appropriate doses of the Nav1.7 inhibitor PF-05089771 and the Nav1.8 inhibitor PF-04885614. Therefore, the composition of the PF-05089771 and the PF-04885614 can be used for treating diseases caused by too high activity of the Nav1.7 or the Nav1.8, and the diseases include but are not limited to intractable pain and itching.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the sodium ion channel Na v 1.7 and Na v 1.8 inhibitors in the treatment of Na v 1.7 and Na v 1.8 Application in diseases caused by excessive activity. Background technique [0002] Neuropathic pain is a kind of intractable pain. The current clinical first-line drugs Gabapentin and Pregabalin can only relieve 40%-60% of patients with neuropathic pain, and have side effects of sedation (such as drowsiness, fatigue, dizziness, etc.) . Therefore, more effective drugs for the treatment of chronic pain are needed to help patients. Voltage-gated sodium channel (Voltage-gated sodium channel, Na v )Na v 1.7 and Na v 1.8 is highly expressed in somatosensory neurons and plays an important role in itching and pain transmission. It is a type of transmembrane glycoprotein complex composed of an α subunit and several β subunits. For example, encoding Na v Gain-of-function mutations...

Claims

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Application Information

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IPC IPC(8): A61K31/427A61K31/417A61P25/06A61P25/04A61P25/02A61P29/00A61P15/00A61P1/02
CPCA61K31/427A61K31/417A61P25/06A61P25/04A61P25/02A61P29/00A61P15/00A61P1/02A61K2300/00A61P17/04A61K31/4164A61K47/02A61K47/36
Inventor 彭长庚孙立婷夏瑞龙
Owner 上海瑞虎康医药合伙企业(有限合伙)
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