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.
Subject(s)
Amides/chemistry , Potassium Channels/agonists , Amides/pharmacology , Amides/therapeutic use , Animals , Cricetinae , In Vitro Techniques , Muscle Contraction , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Rats , Structure-Activity Relationship , Urinary Bladder/drug effects , Urinary Bladder/physiology , Urinary Incontinence/drug therapyABSTRACT
HA-966 (1-hydroxy-3-aminopyrrolidone-2) is an antagonist at the glycine allosteric site of the N-methyl-D-aspartate receptor ionophore complex. Unlike presently known glycine antagonists, HA-966 is chiral. We report stereoselectivity for the (R)-enantiomer at the glycine antagonist site. In [3H]glycine binding, the (R)-enantiomer has an IC50 of 4.1 +/- 0.6 microM. The racemic mixture has an IC50 of 11.2 +/- 0.5 microM, whereas (S)-HA-966 has an IC50 greater than 900 microM. In glycine-stimulated [3H]1-[1-(2- thienyl)cyclohexyl]piperidine binding, the (R)-enantiomer inhibits with an IC50 of 121 +/- 61 microM, whereas the racemic mixture has an IC50 of 216 +/- 113 microM and (S)-HA-966 is inactive. The inhibition by (R)-HA-966 can be prevented by the addition of glycine. (R)-HA-966 and racemic HA-966, but not (S)-HA-966, also prevent N-methyl-D-aspartate cytotoxicity in cortical cultures. The (R)-enantiomer and, less potently, the (S)-enantiomer inhibit N-methyl-D-aspartate-evoked [3H]norepinephrine release from rat hippocampal slices (IC50 values of about 0.3 mM and 1.6 mM, respectively), but only the inhibition by (R)-HA-966 is reversed by added glycine. In glutamate-evoked contractions of the guinea pig ileum, (R)-HA-966 causes a glycine-reversible inhibition (IC50 of about 150 microM), whereas (S)-HA-966 is much less potent (IC50 of greater than 1 mM). These results demonstrate stereoselectivity of the glycine antagonist site of the N-methyl-D-aspartate receptor complex in a variety of tissues and assays. The stereoselectivity also confirms the specificity of N-methyl-D-aspartate receptors in glutamate-evoked contractions of the guinea pig ileum, and supports their similarity to central N-methyl-D-aspartate receptors.
