Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain

Abstract

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

Pharmacological characterization of a novel, potent, selective, and orally active fatty acid amide hydrolase inhibitor, PKM‐833 [(R)‐N‐(pyridazin‐3‐yl)‐4‐(7‐(trifluoromethyl)chroman‐4‐yl)piperazine‐1‐carboxamide] in rats: Potential for the treatment of inflammatory pain

“…URB597 had no improvement on partial sciatic nerve ligation‐induced mechanical allodynia, similar to our finding that PKM‐833 did not significantly attenuate mechanical allodynia in CCI‐induced neuropathic pain. However, brain‐penetrable FAAH inhibitors including URB597 improved spinal nerve ligation‐induced mechanical allodynia at a single systemic administration in rats . Because the effects of FAAH inhibitors on neuropathic pain remain inconclusive, further studies to assess whether a single and/or repeated administration of PKM‐833 can have analgesic potential on other animal models reflecting neuropathic pain accompanied with nerve ligation will be therefore worthwhile.…”

“…Preclinical studies investigated the role of FAAH using FAAH inhibitors and FAAH knockout mice . Several FAAH inhibitors with brain penetration have been subjected to pharmacological analysis and some of them showed analgesic effects on inflammatory and neuropathic pain without undesirable side effects in rat models . They have reached clinical trials to obtain the proof of concept …”

Fatty acid amide hydrolase inhibitors: a patent review (2009 – 2014)

“…Very recently, Merck also described in the scientific literature researches focused on the discovery and development of a class of oxazole inhibitors as possible clinical candidates for inflammatory diseases [104]. They reported the identification of a first pyrazole hit (71, Figure 13) by high-throughput screening (HTS) and the following medicinal chemistry efforts aimed at optimizing both in vitro potency on FAAH and pharmacokinetic properties.…”

“…This led to the discovery of the oxazole 72 (MK-4409, Figure 13), a potent and reversible FAAH inhibitor (IC 50 = 11 nM) devoid of functionalities able to form covalent bonds with the FAAH catalytic site. Compound 72 is effective in animal models of inflammatory (i.e., CFA assay at 10 mg/kg, po) and neuropathic pain (i.e., spinal nerve ligation assay at 3 mg/kg, po) without leading to loss of cognition or motor skill impairment [104].…”

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

“…Selective FAAH inhibitors do not produce either sedative/motor effects or the full gamut of behavioural effects reminiscent of Δ 9 -THC (although individual components of the tetrad test can be affected, the most robust being a modest degree of analgesia in the hotplate test) (see, e.g. Kathuria et al 2003;Solinas et al 2007;Justinova et al 2008;Karbarz et al 2009;Ahn et al 2011;Stewart and McMahon 2011;Chobanian et al 2014). In humans, PF-04457845, at doses producing increases in plasma AEA, OEA and PEA, did not show any effects on cognitive function using a test battery of tasks assessing spatial memory, problem solving, psychomotor function, attention and learning after either 1, 8 or 14 days of treatment (Li et al 2011).…”