N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides:  K_ATP Potassium Channel Openers. Modifications on the Western Region

Abstract

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

Structure-Activity Relationships of KATP Channel Openers

“…Second step was dedicated to achieve in vivo bladder selectivity; the normotensive conscious rat bladder model was used as biological test system that allows the simultaneous measurement of cardiovascular and bladder effects [92,93]. Compounds with large electron withdrawing 4-substituents as present in ZD-6169 68 and in compound 69 exhibit rather high in vivo bladder selectivity, residing in the S-(-)-enantiomers.…”

Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine KATP Channel Activator

“…This latter property is certainly not limited to compounds with such a structural feature, since KATp channel activators have been identified from structural groups as diverse as benzopyrans (1,2), cyanoguanidines (19) and anilide tertiary carbinols (21). Thus, in addition to the therapeutic promise, ZM244085 and compounds from this class could become useful tools from a scientific perspective to help understand and unravel the basic structural features and the modulation site(s) of KATP channels.…”

“…With the tertiary carbinols the hypotensive side effect of a subset of antiandrogen compounds was reinvestigated and shown to be due to K+ channel opening activity (9,21). In the case of the hexahydro-1,8-(2H,SH)-acridinediones, the company collection was searched for unique structures containing a proposed K" channel activator phannacophore, i.e., the perpendicular arrangement of an electron deficient aromatic moiety and hydrogen bond acceptor group present in both low energy conformations (25) and in the X-ray conformation of cromakalim (5).…”

Second-Generation KATP Channel Openers

“…Thus, ZM-226600 23 is a representative of compounds with pronounced KCO, but lacking anti-androgen activity. Second step was dedicated to achieve in vivo bladder selectivity; the normotensive conscious rat bladder model was used as biological test system that allows the simultaneous measurement of cardiovascular and bladder effects [69,70]. Compounds with large electron withdrawing 4-substituents as present in 24 and 25 exhibit rather high in vivo bladder selectivity, residing in the S-(-)-enantiomers.…”

“…KCO properties of ZD-6169 were intensively studied in vitro and in vivo [37,[67][68][69][70][71][72] Recent studies on the mechanism of the bladder-selective actions of ZD-6169 suggest the involvement of an inhibitory effect on bladder C-fiber afferents in addition to KCOs properties. After intravesical infusion, ZD-6169 blocked acetic acid-induced bladder overactivity in a similar manner as the C-fiber afferent neurotoxin capsaicin [73].…”