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.

Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

The reaction of allylic chlorides with pyrimidine nucleoside derived organopalladium intermediates was investigated. The organopalladium intermediates were generated in situ by the reaction of 5-(chloromercuri)-2'-deoxyuridine (1), 5-(chloromercuri)cytidine, and 5-(chloromercuri)-2'-deoxycytidine with a catalytic amount of Li2PdCl4 in methanol. With allyl chloride, 1 gives principally 5-allyl-2'-deoxyuridine, some of which reacts further with 1 to give the cross-linked nucleosides (E)-5-[3-(2'-deoxyuridin-5-yl)T-propen-l-yl]-2'-deoxyuridine (5) and 5-[3-(2'-deoxyuridin-5-yl)-l-methoxyprop-l-yl]-2,-deoxyuridine (6). 3-Chloro-l-butene couples with 1 to give mainly (£)-5-(2-buten-l-yl)-2'-deoxyuridine (9) and lesser amounts of the Z isomer 10 and 5-(l-

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