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Voltage-gated calcium channel (Ca v )2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca v 2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca v 2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca v 2.2 channels under depolarized conditions (IC 50 ϭ 0.27 M) compared with hyperpolarized conditions (IC 50 Ͼ 20 M). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited -conotoxin GVIA-sensitive calcium currents (Ca v 2.2 channel currents), with greater potency under depolarized conditions (IC 50 ϭ 0.4 M) than under hyperpolarized conditions (IC 50 ϭ 2.6 M), indicating state-dependent Ca v 2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca v 2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca v 2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca v 2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20-to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca v 2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.Inflammatory diseases and neuropathic insults are frequently accompanied by severe debilitating pain, which can become chronic and unresponsive to conventional analgesic treatments. Intrathecal administration of conventional agents, including morphine, may be required in more severe C.A. and O.B.M. contributed equally to this work. Article, publication date, and citation information can be found at

ABSTRACT:We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays. KEYWORDS:Fatty acid amide hydrolase, FAAH, oxazole, pyrazole, neuropathic pain, inflammatory pain, MK-4409, enzyme, inhibitor, CNS F atty acid amide hydrolase (FAAH) is an integral, membrane-bound enzyme responsible for the breakdown of fatty acid ethanolamide (FAE) signaling molecules, such as the endocanabinoid arachidonyl ethanolamide (anandamide, AEA), N-palmitoyl ethanolamide (PEA), and N-oleoyl ethanolamide (OEA). FAAH is a member of the serine hydrolase amidase signature family, which utilizes an unusual serine−serine−lysine catalytic triad. 1,2 Inhibition of FAAH leads to elevated levels of these endogenous FAEs, which act on cannabinoid receptors implicated in the suppression of pain transmission. 3 Levels of these FAEs were shown to be significantly elevated in FAAH knockout (KO) mice as compared to wild-type controls. 4 Both genetic knockout of FAAH and pharmacological modulation of FAAH activity demonstrated reduced sensitivity to pain. 5 Thus, FAAH inhibitors are expected to provide therapeutic benefits in the management of inflammatory and neuropathic pain. 6−9 Several classes of covalent and noncovalent FAAH inhibitors have been reported to date (Figure 1). Several covalent FAAH inhibitors that irreversibly inhibit FAAH by carbamylation of Ser241 have been reported and are exemplified by [10][11][12] A second subclass of FAAH inhibitors are the keto-oxazole class of FAAH inhibitors as exemplified by OL-135, 13 which reversibly forms an enzymestabilized hemiketal through a particularly reactive electrophilic carbonyl. More recently, however, several scaffolds have been disclosed as reversible noncovalent modifying inhibitors of

The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.

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ABSTRACT:We report the investigation of sulfonamidederived Ca v 2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)-benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Ca v 2.2 potency without the liability of the circulating sulfonamide metabolite. KEYWORDS: Ca v 2.2, N-type calcium channel, pain, sulfonamide, bioisostere, sulfone N -Type calcium channels (Ca v 2.2) are expressed in the presynaptic termini of primary afferent nociceptors in the spinal cord and are key components of the pain transmission pathway. We have previously reported the discovery of a series of aminopiperidine sulfonamide state-dependent Ca v 2.2 channel inhibitors with potential utility for the treatment of chronic pain. Members of this class are orally bioavailable and efficacious in preclinical pain models. 1 In particular, 1 ( Figure 1) is selective for inhibition of the Ca v 2.2 channel over the cardiovascular ion channels hERG and Ca v 1.2, with a decent preclinical PK and biodistribution profile. The compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia, but it has no efficacy in Ca v 2.2 gene-deleted mice. The compound is also devoid of ancillary preclinical cardiovascular or CNS pharmacology. While 1 may be used as a preclinical tool to evaluate state-dependent inhibition of Ca v 2.2 channels, it has several drug metabolism related issues that confound further development of the compound. These include moderate CYP3A4 inhibition (IC 50 = 5.1 μM), PXR activation (EC 50 = 0.43 μM), and the formation of the persistent circulating metabolite 2. The sulfonamide metabolite 2 exhibited preclinical antinociceptive activity in its own right, although it was devoid of significant Ca v 2.2 activity. In order to further improve this lead class of Ca v 2.2 inhibitors and address the drug metabolism issues associated with this series, SAR optimization studies were carried out on the amide substituent and the aminopiperidine core, and a bioisostere replacement strategy was pursued for the sulfonamide moiety.The first substituent to be investigated for further optimization was the benzoic amide moiety (Table 1). The synthesis of piperidine sulfonamide compounds listed in Table 1 was straightforward as described previously. 1 This synthetic route allowed rapid SAR studies modifying substitutions on the benzamide phenyl ring. In some instances, the desired benzoic acid partner had to be synthesized. For example, the intermediate 4-(methylsulfonyl)-2-trifluoromethoxy-benzoic

Based on our in vitro and in vivo findings and until further clinical drug interaction experiments are conducted, the co-administration of drugs, especially those primarily cleared via CYP2D catalyzed metabolism, with T. arjuna extracts should be done with caution.