Structure-activity studies of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.

A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP).

Effects of substitution on 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4- azacyclopenta[b]naphthalene-1,8-dione, a dihydropyridine ATP-sensitive potassium channel opener.

Structure-activity relationships were investigated on the tricyclic dihydropyridine (DHP) KATP openers 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (6) and 10-(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk- cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an electrically stimulated pig bladder strip assay.

In vitro and in vivo characterization of a novel naphthylamide ATP-sensitive K+ channel opener, A-151892.

1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl]-acetamide (A-151892), as an opener of the ATP-sensitive potassium channels.

Synthesis and structure-activity relationships of a novel series of tricyclic dihydropyridine-based KATP openers that potently inhibit bladder contractions in vitro.

Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay.

Synthesis and structure-activity relationships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide K(ATP) channel openers: discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9- hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a potent K(ATP) opener that selectively inhibits spontaneous bladder contractions.

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds.

Structure-activity studies for a novel series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones as K(ATP) channel openers.

In search of a novel chemotype of K(ATP) channel openers a series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones was synthesized. It was found that cyclopentanone in the left hand portion of the molecule was 4-fold more potent than cyclohexanone. Introduction of gem-dimethyl groups as well as incorporation of oxygen in the cyclohexanone ring in the left hand portion of the molecule increased the potency 10-fold.

Characterization of human urinary bladder KATP channels containing SUR2B splice variants expressed in L-cells.

The molecular properties of the sulfonylurea receptor 2 (SUR2) subunits of K(ATP) channels expressed in urinary bladder were assessed by polymerase chain reaction (PCR). This showed that SUR2B exon 17- mRNA (72%) was predominant over the SUR2B exon 17+ splice variant (28%). The pharmacological properties of both of these isoforms stably expressed in mouse Ltk(-)cells (L-cells) with K(IR) 6.

Design and synthesis of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.

Thiourea derivatives were identified as glyburide-reversible potassium channel openers through high-throughput screening. Based on these findings, a number of novel cyanoguanidines were designed and synthesized, which hyperpolarized human bladder K(ATP) channels. These agents are potent full agonists in relaxing electrically-stimulated pig bladder strips.

[125I]A-312110, a novel high-affinity 1,4-dihydropyridine ATP-sensitive K+ channel opener: characterization and pharmacology of binding.

Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihydropyridine KATP channel opener, [125I]A-312110 [(9R)-9-(4-fluoro-3-125iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one-1,1-dioxide]. Binding of [125I]A-312110 to guinea pig cardiac (KD = 5.

Pharmacological characterization of a 1,4-dihydropyridine analogue, 9-(3,4-dichlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (A-184209) as a novelK(ATP) channel inhibitor.

1. This study reports on the identification and characterization of a 1,4-dihydropyridine analogue, 9-(3,4-dichlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (A-184209) as a novel inhibitor of ATP-sensitive K(+) channels. 2.

(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. I. In vitro characterization.

Alterations in the myogenic activity of the bladder smooth muscle are thought to serve as a basis for the involuntary detrusor contractions associated with the overactive bladder. Activation of ATP-sensitive K(+) (K(ATP)) channels has been recognized as a potentially viable mechanism to modulate membrane excitability in bladder smooth muscle. In this study, we describe the preclinical pharmacology of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel 1,4-dihydropyridine K(ATP) channel opener (KCO) that demonstrates enhanced bladder selectivity for the suppression of unstable bladder contractions in vivo relative to other reference KCOs.

Structure-Activity studies for a novel series of tricyclic dihydropyrimidines as K(ATP) channel openers (KCOs).

A novel series of tricyclic dihydropyrimidines was synthesized and evaluated for activity as K(ATP) channel openers. The functional activity of several compounds, for example 6A (EC(50)=30nM) and its enantiomers exceeded cromakalim.

Functional characterization of adenosine receptors and coupling to ATP-sensitive K+ channels in Guinea pig urinary bladder smooth muscle.

Although multiple adenosine receptors have been identified, the subtype and underlying mechanisms involved in the relaxation response to adenosine in the urinary bladder remain unclear. The present study investigates changes in the membrane potential, as assessed by fluorescence-based techniques, of bladder smooth muscle cells by adenosine receptor agonists acting via ATP-sensitive potassium (K(ATP)) channels. Membrane hyperpolarization evoked by adenosine and various adenosine receptor subtype-selective agonists was attenuated or reversed by the K(ATP) channel blocker glyburide.