Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator

Abstract

A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC(50)=260 nM). ML277 was shown to be highly selective against other KCNQ channels (>100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel.

Figure 1

Literature reported activators of KNCQ1.

Figure 2

Structure of the initial HTS hit.

Scheme 1

(a) HATU, DIEA, DMF, 4-(4-methoxyphenyl)thiazol-2-amine (7) (42–77%), (b) TFA, DCM, (c) RSO₂Cl (or ROCl), TEA, DCM.

Scheme 2

(a) p-TsCl or p-chlorophenylSO₂Cl, TEA, DCM (R = CH₃, 57–72%; R = Cl, 37 – 43%); (b) R¹NH₂, HATU, DIEA, DMF; (c) HATU, DIEA, DMF (R = CH₃, 12–79%; R = Cl, 19–75%); (d) R²B(OH)₂, K₃PO₄, Pd(OAc)₂, THF:H₂O, 80 °C.