Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic Pain

Abstract

Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (4), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure−activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties.Compound 58, a central pyridine isomer of BMS-986176/LX-9211 (4), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to 4 in the CCI rat model. However, both 43 and 58 showed an inferior preclinical toxicity profile compared to 4.

Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain

“…In summary, we have discovered a novel class of bi­(hetero)­aryl ether derivatives as highly potent and selective AAK1 inhibitors. Extensive SAR around the bi­(hetero)­aryl core led to the identification of multiple analogs with good inhibitory activity . Within this series, compound 34 (BMS-986176/LX-9211) demonstrated good efficacy in two rat models of neuropathic pain at oral doses of 0.3–1 mg/kg.…”

“…Extensive SAR around the bi(hetero)aryl core led to the identification of multiple analogs with good inhibitory activity. 35 Within this series, compound 34 (BMS-986176/LX-9211) demonstrated good efficacy in two rat models of neuropathic pain at oral doses of 0.3−1 mg/kg. The efficacy seen with 34 in the CCI model correlated well with the spinal cord occupancy.…”

“… Much broader SAR variations on this pyridine-phenyl core were performed to optimize the potency and overall properties of these analogs. Accordingly, herein and in an accompanying paper, we describe the SAR studies of this series that ultimately lead to the discovery of ( S )-1-((2′,6-bis­(difluoromethyl)-[2,4′-bipyridin]-5-yl)­oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) ( 34 ) that is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).…”

Reductive Catalytic Difluorocarbene Transfer via Palladium Catalysis

“…Remarkably, substrates bearing two carbon electrophiles were also competent coupling partners, with aryl bromide as the primary reaction site. For instance, aryl bromide bearing a benzylic carbonate ester (7) or pchloroaryl bromide ( 14) underwent the current coupling smoothly. In particular, the highly active benzylic carbonate ester, prone to generate a benzylpalladium complex through oxidative addition, did not provide the benzyldifluoromethane (7), demonstrating the high chemoselectivity of this protocol.…”

Discovery of 4-(1,2,4-Oxadiazol-5-yl)azepan-2-one Derivatives as a New Class of Cannabinoid Type 2 Receptor Agonists for the Treatment of Inflammatory Pain

“…Receptor targets such as vanilloid receptor 1 (TRPV1), α2A-adrenergic receptor (α2AAR), cannabinoids, , P2X3 and P2X7, − N -methyl- d -aspartate (NMDA), A3 adenosine receptors, and adaptor protein-2 associated kinase 1 (AAK1) − as well as ion channels like the voltage-gated sodium channel Nav1.7 and high-voltage-activated calcium channels (HVACCs) have been targeted for the development of novel analgesics . Among them, targeting cannabinoids is a promising option for pain alleviation, particularly in the treatment of arthritis-associated pain, not only because of their analgesic effect but also their anti-inflammatory and anti-apoptotic properties.…”