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

Abstract

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2′,6-Bis­(difluoromethyl)-[2,4′-bipyridin]-5-yl)­oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi­(hetero)­aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

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

“…As indicated in a previous report, adding a methyl group next to the amino group on the side chain helped reduce CYP3A4 inhibition. Combinations of this tertiary amino side chain with the acetyl amide pyridine hinge binding group were explored, and the data for select analogues ( 21 – 25 ) are listed in Table .…”

“…As described in the preceding paper and detailed in the Experimental Section, the inhibitory activity of target compounds toward AAK1 was assessed as AAK1 IC 50 . The target compounds were tested in a radioactive displacement assay, and the data was reported as Filt K i .…”

“…The b/p ratio of 8 was measured to be 0.45, while the b/p ratio of analogue 10 was higher at 1.5 (2 h post dose). In the chronic constriction injury (CCI)-induced model in rats, loose ligatures are tied around the sciatic nerve to simulate the conditions of nerve compression injury. , This procedure results in the development of hyperalgesia and allodynia, which is measured 2–4 weeks after surgery . Compound 10 was tested in this CCI-induced thermal hyperalgesia rat model, with LP-935509 ( 1 ) as a positive control, and showed peak efficacy of around 56% when dosed at 1 mg/kg, p.o.…”

“…Thermal hyperalgesia was measured by the Hargreaves test, in which the rat paw withdrawal latency was recorded following application of a noxious light source to the plantar surface of the hindpaw . Compound 10 was also tested in the streptozotocin (STZ)-induced diabetic peripheral neuropathic pain (DPNP) mechanical allodynia rat model. ,, Specifically, male Sprague-Dawley rats were fasted overnight and then treated with 50 mg/kg STZ. Rats were allowed food 1 h after STZ treatment and were monitored for the next 48 h for any symptoms of hypoglycemia.…”

“…Most recently, AAK1 inhibitor 3 from a structurally differentiated chemotype was shown to be efficacious in rodent neuropathic pain models without motoric side effects, lending further support for AAK1 as a viable target for treating neuropathic pain . In the proceeding report, we disclosed BMS-9861762/LX-9211 ( 4 ) as a highly selective, CNS-penetrable, and orally active AAK1 inhibitor in clinic trials for treating neuropathic pain . During the course of structure–activity relationship (SAR) studies, it was found that compounds with an extra hydrogen-bond donor at the hinge binding site (Figure ) had good AAK1 inhibition potency.…”