Acute or chronic pain is one of the most widespread and frequent human complaints, as well as one of the most difficult syndromes to treat successfully with drugs or surgery. Some types of acute or chronic pain are particularly related to neuropathic and/or neurogenic inflammation. Such neurogenic inflammation can be triggered by the activation of unmyelinated sensory neurons through noxious stimuli and the subsequent release of neuropeptides such as calcitonin gene-related peptide (CGRP, U.S. Pat. No. 4,549,986) and substance P (SP) from the peripheral nerve endings of these nociceptive neurons (Amara, et al., 1982; Nassini, et al., 2014). Additionally, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to further liberate CGRP and SP in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain through activation of their receptors (Trevisan, et al., 2014).
Isoform α-CGRP, a 37 amino acid peptide, is generated from a specific splicing of calcitonin and synthesized in the somata of nociceptive neurons in the dorsal root ganglion (DRG). α-CGRP and β-CGRP can be transported to the peripheral and central nerve endings where it can be released upon intensive activation of those afferents (Boulanger, et al., 1995). CGRP has been found in approximately 50% of C fibers and 35% of Aδ-fibers. When released from nerve terminals, α-CGRP or β-CGRP binds to a heteromeric receptor of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein 1 (RAMP1), and increases nociceptive sensitivity in response to non-noxious mechanical and thermal stimuli under normal conditions.
Under pathological conditions, excessively released CGRP prolongs and enhances vasodilatation and plasma extravasation initiated by inflammatory mediators such as histamine, prostaglandins (e.g., PGE2), and cytokines. Thus, excessive CGRP produces thermal hyperalgesia and mechanical allodynia, a condition in which pain is induced by otherwise non-noxious stimuli, and plays a critical role in development of neurogenic inflammatory and chronic pain. For example, CGRP released from the C-fibers projecting from the trigeminal ganglion to the cerebral meninges (outer brain liner) has been suggested to play a crucial role in the pathophysiology of headaches, particularly migraines. TRPV1 agonist capsaicin evokes a concentration-dependent increase in CGRP release in rat trigeminal ganglia slices. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain. Furthermore, overexpression of CGRP has been found in migraine and temporomandibular joint (TMJ) disorder.
In preclinical research, using a gene knockout approach, mice lacking CGRP display an attenuated response to chemical-induced pain and inflammation. Using antisense sequence to knock down CGRP specifically in sensory neurons produced a reduction of CGRP levels, and also a decrease in the behavioral hyperalgesia that resulted from capsaicin treatment (Tzabazis et al., 2007). The N-terminal amino acids 1-7 are required for receptor activation and signal transduction, whereas the remainder (amino acids 8-37) of CGRP is necessary for receptor binding. Thus, a polypeptide that contains only amino acids 8-37 of CGRP (CGRP8-37) can act as a CGRP receptor antagonist. Intravenous (i.v.) of a variety of anti-CGRP antibodies and i.v. or intrathecal (i.t.) administration of human CGRP 8-37, a 31 amino acid fragment of CGRP that lacks seven N-terminal amino acids has been found to significantly attenuate chemical (e.g., capsaicin or acetic acid as well as CGRP)-induced hypersensitivity via blockade of CGRP receptors (Plourde, et al., 1997, and U.S. Pat. No. 6,268,474; WO 2007048026 A2; WO 2007048026 A2; WO 2009/109911; US 20110054150 A1).
In clinical studies, migraine therapeutics sumatriptan and donitriptan have been demonstrated to inhibit CGRP release as well as to prevent or attenuate associated neurogenic inflammation. CGRP-mediated neurogenic dural vasodilation is blocked by dihydroergotamine, triptans, and opioids, all of which have demonstrated clinical efficacy against migraines. The systemic administration of CGRP receptor antagonists CGRP 8-37, BIBN4096 and MK-0974 were under investigation in clinical trials, and initial results indicated that BIBN4096, MK-0974, MK-3207 and BI 44370 alleviated acute migraine headache (Troconiz, et al., 2006; Farinelli, et al., 2009; Nieber, 2009; Edvinsson and Warfvinge, 2013; Hostetler, et al., 2013).
Both preclinical data and clinical evidence obtained using a systemic approach of antagonism of CGRP suggest the site of action is via a central mechanism (Troconiz, et al., 2006; Edvinsson and Warfvinge, 2013; Hostetler, et al., 2013). Systemic antagonism of CGRP often produced undesirable side effects leading to suspension of clinical trials of small molecule CGRP antagonists (Benemei, et al., 2009; Edvinsson and Warfvinge, 2013).
Nerve or tissue injury, trauma or inflammation triggers release of neuropeptides including CGRP from afferent nerve endings, and in turn CGRP enhances nociceptive neuronal activity. Therefore, local injection (e.g., cutaneous injection) of voltage-gated sodium (Na) channel blockers such as lidocaine or bupivacaine have long been used to inhibit local pain sensitivity, such as that following surgery. However their action usually lasts for only a few hours and mainly relieves acute nociceptive pain. The naturally occurring sodium channel blocker saxitoxin in animals such as fish and crabs has been shown to be much more potent in blocking sodium currents in rat DRG neurons than lidocaine. However, because of undesired systemic side effects, saxitoxin cannot be administered systemically. Local administration of saxitoxin has not been trialed in clinic. In clinical trials, scalp injections of botulotoxin A (Botox) have been shown to be effective as a local treatment for migraine, presumably by blocking release of pronociception chemicals including CGRP from nociceptive afferents. Although this procedure may provide peripheral therapy for migraine, Botox also paralyzes skeletal muscles, which may lead to unwanted side-effects (except for its currently approved local cosmetic use).
The pathophysiology of excessive CGRP has now been recognized as a key contributing factor in acute or chronic pain with known or uncertain etiology in humans, such as postoperative pain (surgical or incision pain), neuromas, migraines, radiation pain, diabetic neuropathic pain, primary erythromelalgia and secondary erythromelalgia (resulting from a variety of disorders or toxications), and complex regional pain syndrome, etc. (Herbert and Holzer, 2002).
Current systemic pharmacological therapeutics for migraine and neuropathic pain include the triptans (serotonin 5-HT1B/1D agonists, e.g. sumatriptan), non-steroidal anti-inflammatory drugs (NSAIDs, e.g. tramadol), anti-convulsants (e.g. carbamazepine and lamotrigine), antidepressants (e.g. amitryptiline and duloxetine), narcotics (e.g. oxycodone) and anti-neuropathic pain drugs (gabapentin and pregabaline). However, none of these treatment options provides acceptable systemic pain relief for more than 50% of the treated patients. In addition, all of these drugs are known to have undesirable systemic side effects (Uhl, et al., 2014). Therefore, there is a need for compounds are more effective and safer analgesics and/or anti-inflammatories. In addition, there is a need for improved means of delivering such drugs to the body to reduce systemic side effects and avoid toxicity. The present invention provides such compounds.
USPTO Backgrounds
USPTO Backgrounds