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Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.

Neuronal nicotinic acetylcholine receptors (nAChRs) have been a target for drug discovery efforts, primarily for CNS indications, for the past two decades. While nicotine and related natural products have been used for smoking cessation in various formulations (e.g., gum, spray, patches), it was only in 2006 with the launch of varenicline (Chantix) by Pfizer for smoking cessation that a new chemical entity (NCE) originating from a rational medicinal chemistry effort targeting neuronal AChRs was approved. The current overview outlines the chronology of drug discovery efforts in nAChRs from the cloning of the receptor family in the 1980s, to initial research efforts at SIBIA, R.J. Reynolds and Abbott, to the current industry-wide interest in nAChR agonists as novel therapeutics for pain, schizophrenia and Alzheimer's Disease. Key events in the evolution of the nAChR field were the development of high throughput electrophysiological screening tools that provided the means to enable lead optimization efforts in medicinal chemistry and the discovery by John Daly at the NIH of the frog alkaloid, epibatidine, that provided the framework for the discovery of ABT-594, an alpha4beta2 agonist that is 200 times more potent than morphine as an analgesic. Over the next decade, it is anticipated that additional NCEs including antagonists and allosteric modulators (both positive and negative), interacting with various nAChR subtypes, will be advanced to the clinic in areas of high unmet medical need, e.g., pain, neurodegeneration, to provide novel medications with improved efficacy.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.

Structure−activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing KATP openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for KATP 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. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (−)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective KATP channel openers may have utility ...

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.

Chapter 6 addresses the mechanism of action of agents that target nucleic acids (DNA or RNA) to achieve their biological effects. First, the key structural properties of nucleic acids that account for their interactions with small molecules are discussed. Then the mechanisms of action of antitumor antibiotic agents are discussed according to whether they act as reversible binders (including groove binders and DNA intercalators), as alkylators (including metabolically-activated alkylating agents), or as DNA strand breakers, including a discussion of the mode of action of a number of naturally-occurring antitumor antibiotics (anthracyclines, bleomycin, tirapazamine, and enediynes).

Chapter 7 first discusses various mechanisms that can account for drug resistance and examples of approaches used to circumvent it. Mechanisms of resistance that are highlighted include altered drug target, overproduction of the target protein, overproduction of substrate or ligand, increased drug-destroying mechanisms, decreased prodrug activation, new pathways that circumvent drug action, reversal of drug action, and altered drug distribution to the site of action. A separate section discusses drug synergism and various approaches used to capitalize on synergism for improved therapeutic effects or enhanced safety margin. Specific topics of drug synergism include inhibition of a drug destroying enzyme, sequential blocking, inhibition of multiple pathways, efflux pump inhibition, and use of multiple drugs for the same target.

Chapter 9 focuses on the prodrug approach to overcoming problems frequently encountered in drug design, such as poor solubility or absorption, short duration of action, toxicity, patient acceptability, formulation problems, or impaired access to the site of action. Building from the foundation laid by Chapter 8, Chapter 9 describes how various intrinsic metabolic processes can be harnessed to promote release of the active drug from its prodrug form, often at or near the intended site of action. Two types of prodrug approaches, the attachment of a small molecule or macromolecular carrier group to the drug and modification of the drug to a masked form, are described.

Chapter 4 introduces enzymes, which collectively represent a highly influential special class of receptors, and which comprise several major classes of protein drug targets. Mechanisms that account for the catalytic action of enzymes are extensively covered, together with the detailed mechanisms of action of key coenzymes, including pyridoxal 5′-phosphate, tetrahydrofolate, pyridine nucleotides, flavin, heme, and ATP. Enzymes used in drug synthesis and those that can serve as therapeutic agents, rather than as drug targets, also are discussed.

The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules. This new edition reflects significant changes in the process of drug design over the last decade. It preserves the successful approach of the previous editions while including significant changes in format and coverage.

Building on the concepts provided in Chapters 3 and 4 Chapter 3 Chapter 4, this chapter focuses on the mechanism of action of enzyme inhibitors and enzyme inactivators and their consequent usefulness as drugs. With extensive use of examples and case histories, several subcategories of reversible inhibition are covered, including competitive inhibition, stabilization of an enzyme conformation, substrate mimicry, transition state mimicry, and slow, tight-binding inhibition. Irreversible enzyme inhibition, including the subcategories of affinity labeling and mechanism-based inactivation, is discussed with the use of multiple examples.

Chapter 2 focuses, in detail, on the many considerations encountered in lead discovery and lead modification stages of modern rational drug design, as typically practiced in pharmaceutical companies and many academic research laboratories. Examples emphasize how the concepts of organic chemistry are applied during the practice of these key stages of drug discovery. Major topics of discussion are the various sources for lead compounds, including virtual screening, computational methods, and fragment-based approaches, and desired properties of lead compounds. This is followed by an exploration of the objectives, considerations, and methods for subsequently optimizing lead compounds across multiple parameters such as potency, selectivity, and ADME properties. Approaches for the identification of the pharmacophore and for the determination of structure-activity relationships, including quantitative and other computational and molecular graphics-based methods, are discussed, and properties important to oral bioavailability and membrane permeability are described.

Chapter 3 discusses concepts of macromolecular receptors as drug targets. Attention is directed at the molecular forces that drive the interactions of a drug with its target receptor. The concepts of receptor agonism, partial agonism, inverse agonism, and antagonism are discussed, and theories of how small molecules exert their effects on receptors, and consequently on the cells and tissues that express them, are described. In addition, the important concepts of topography and stereochemistry, as related to drug-receptor interactions, are introduced, and various molecules with stereochemical features, such as enantiomers, diastereomers, conformational isomers, atropisomers, and ring compounds, are discussed in detail. Two receptor-related case histories, one driven by receptor binding and the other driven by pharmacokinetics, are presented.

A concise asymmetric synthesis of ( R )-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594) is presented in which the key intermediate t -butoxycarbonyl protected (2 R )-azetidinylalcohol is obtained in three steps from the dibenzyl ester of D-aspartic acid in 44% yield and >99% ee.

ABT-594, a nicotinic acetylcholine receptor agonist, has antinociceptive effects in rat models of acute thermal, persistent chemical, and neuropathic pain. Direct injection of ABT-594 into the nucleus raphe magnus (NRM) is antinociceptive in a thermal threshold test and destruction of serotonergic neurons in the NRM attenuates the effect of systemic ABT-594. However, lidocaine-inactivation of the NRM prevents the antinociceptive effect of systemic (-)-nicotine but not that of systemic ABT-594.

Analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine (A-84543, 1) with 2-, 4-, 5-, and 6-substituents on the pyridine ring were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 9,000 nM when tested in vitro for neuronal nicotinic acetylcholine receptor binding activity. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors indicates that pyridine substitution can have a profound effect on efficacy at these subtypes, and several subtype-selective agonists and antagonists have been identified.

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

A novel series of 2-(2′-furo[3,2-b]pyridinyl) pyrrolidines has been synthesized and evaluated as novel nicotinic acetylcholine receptor ligands. Changing the pyrrolidine stereochemistry and N-substitution pattern afforded analogs with Ki values ranging from 2.7 to 97 nM. Rubidium efflux studies revealed that these compounds had intrinsic activities ranging from 9–58% that of nicotine in the IMR-32 cell line and 6–81% in the K177 cell line. The N(Me)-2(S) analog 3a demonstrated good selectivity in the K177 cell line (α4β2 receptor) versus the IMR-32 cells (α3βx receptor) and TE 671 cells (α1 neuromuscular receptor), and was a partial agonist with an EC50 value of 141 nM in dopamine release assay using rat striatal slices.

ABT-089 [3-(2(S)-pyrrolidinylmethoxy)-2-methylpyridine] is a cholinergic channel modulator (ChCM) that selectively affects the function of neuronal nicotine acetylcholine receptor (nAChR) subtypes, enhances cognitive performance and has neuroprotective activity. Previous reports indicate that, unlike the other nicotinic receptor ligands, ABT-418 and (-)- nicotine, ABT-089 exhibits a more complex profile, having agonist, partial agonist, and inhibitory activities depending on the putative nAChR subtype with which it interacts. This study provides safety and pharmacokinetic information that clearly differentiate ABT-089 from both (-)-nicotine and ABT-418. ABT-089 has a reduced activation of ganglionic nAChRs, resulting in a reduced propensity to elicit side effects at high doses. Studies using guinea pig ileum indicate that ABT-089, in contrast to (-)- nicotine and the muscarinic agonist,methacholine, has no detectable effects on smooth muscle contractility, suggesting low potential for interference with gastrointestinal mobility. ABT-089 is orally available (33–76% in rat, dog, and monkey) and preliminary formulation data indicates that once-a-day formulation is feasible. In contrast, ABT-418 and (-)-nicotine have poor oral bioavailability in dog and monkey (

A series of 2-(aryloxymethyl) azetidine and pyrrolidine nAChR ligands in which the 3-pyridyl moiety of a previously described series 1 was replaced by a substituted phenyl group was explored. Aromatic substitution afforded analogues with K i values ranging from 3 to >10,000 nM. Generally, substitution at the ortho - and para -position was unfavorable, whereas electron-withdrawing groups at the meta -position improved the K i values.

The development of a novel series of carbamoylamino acid benzoylpiperidides as CCK B ligands is described. Selected members of the series antagonized CCK 8 -induced calcium mobilization and showed efficacy in the mouse elevated-plus maze, a measure of potential anxiolytic activity.

The ability of nicotine to enhance cognition in animals and humans and to exert neuroprotective and anxiolytic-like effects, as well as the negative correlation between smoking and Alzheimer's (and Parkinson's) disease, suggest a possible role for nicotinic agents in the treatment of some of the deficits that result from these conditions. Numerous compounds are known which activate neuronal nicotinic acetylcholine receptors (nAChRs) and which might serve as lead compounds toward the development of such agents. The diversity of nAChRs suggests the possibility of developing selective compounds which would have more favorable side-effect profiles than the existing agents. An overview of the nicotinic system and model systems used to study nicotinic receptors is presented, followed by a discussion of structure–activity relationships of known lead compounds in assays that are thought to reflect therapeutic potential or possible side effects. © 1995 Wiley-Liss, Inc.

A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non–small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAFV600E (Kd BRAFV600E = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal–regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC50 = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAFV600E versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10–55 mg/kg) of both pMEK and pERK in BRAFV600E colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30–100 mg/kg twice daily) against BRAFV600E melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development. Mol Cancer Ther; 11(4); 930–41. ©2012 AACR.

N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1) is a novel α1 agent having the unique profile of α1A (rabbit urethra, EC50 = 0.60 μM) agonism with α1B (rat spleen, pA2 = 5.4) and α1D (rat aorta, pA2 = 6.2) antagonism. An in vivo dog model showed 1 to be more selective for the urethra over the vasculature than A-61603 (2), ST-1059 (3, the active metabolite of midodrine), and phenylpropanolamine (4).

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.

Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.

New and existing methodologies were used to prepare a series of modified CCK analogs in which each amide bond was replaced by a trans-alkene unit. The data indicate that every amide linkage at C-terminal tetrapeptide (CCK-4) region is crucial for biological activity. While the amide bond beyond the Trp residue in the N-terminal direction can be replaced by a trans-alkene and still retain most of the binding potency and functional activity.

In an effort to probe the steric influence of C5 substitution of the pyridine ring on CNS binding affinity, analogues of 1 substituted with a bulky moiety—such as phenyl, substituted phenyl, or heteroaryl—were synthesized and tested in vitro for neuronal nicotinic acetylcholine receptor binding affinity. The substituted analogues exhibited K i values ranging from 0.055 to 0.69 nM compared to a K i value of 0.15 nM for compound 1 . Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors led to identify several agonists and antagonists.

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

A novel series of 2-(2′-furo[3,2-b]pyridinyl) pyrrolidines has been synthesized and evaluated as novel nicotinic acetylcholine receptor ligands. Changing the pyrrolidine stereochemistry and N-substitution pattern afforded analogs with Ki values ranging from 2.7 to 97 nM. Rubidium efflux studies revealed that these compounds had intrinsic activities ranging from 9–58% that of nicotine in the IMR-32 cell line and 6–81% in the K177 cell line. The N(Me)-2(S) analog 3a demonstrated good selectivity in the K177 cell line (α4β2 receptor) versus the IMR-32 cells (α3βx receptor) and TE 671 cells (α1 neuromuscular receptor), and was a partial agonist with an EC50 value of 141 nM in dopamine release assay using rat striatal slices.

A concise asymmetric synthesis of ( R )-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594) is presented in which the key intermediate t -butoxycarbonyl protected (2 R )-azetidinylalcohol is obtained in three steps from the dibenzyl ester of D-aspartic acid in 44% yield and >99% ee.

A series of modifications of the CCK7 analogue (des-NH2)Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2 was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally restricted residues in the C-terminal tetrapeptide region, including delta Z-Phe33, (N-Me)Phe33, (N-Me)Asp32, (N-Me)Leu31, and 3PP31 (3PP = trans-3-n-propyl-L- proline) were found to be acceptable modifications at one or both receptor subtypes. The (N-Me)Asp32 and (N-Me)Leu31 modifications afforded potent and selective CCK-A and CCK-B ligands, respectively. SAR studies in the N-terminal acyldipeptide region examined structural requirements for the side chain at position 28, where Gly and Pro replacements were found to possess high affinity at both receptor subtypes. Other conformationally restrictive modifications were less active. All of the analogues that showed high affinity (less than 10 nM) for the CCK-A receptor also were full agonists in amylase release and most were full or nearly full agonists in the phosphoinositide (PI) turnover assay, the most notable exception being the delta Z-Phe33 analogue, which showed 69% of the maximal response in the PI assay. Potent activity in suppression of food intake in rats was found for selected analogues.

The ready availability of N-(trifluoroacetyl)-α-allylphenylalaninamide (4) via a dehydration/hetero-Cope rearrangement/ammonolysis sequence starting with N-(trifluoroacetyl) phenylalanine allyl ester made it an attractive intermediate for elaboration into C-α to N- or C-α to N'-bridged products as conformationally restricted phenylalaninamide analogues. Oxidative one-carbon degradation of the side-chain olefin followed by acid-catalyzed silane reduction afforded C-α to N'-bridged γ-lactam. Hydroboration/oxidation of the side-chain olefin provided an intermediate that could be cyclized selectively either to a δ-lactam or a proline analogue depending on choice of dehydrating conditions. For preparation of a target dipeptide containing the α-substituted proline moiety, a preferred route involved N-deprotection of 4 and coupling to Boc-Asp(OBn)-OH to give a dipeptide intermediate, which similarly could be elaborated selectively to either the α-benzyl δ-lactam analogue or the α-benzylproline analogue

La modification apportee dans la synthese de prolines substituees en 3 consiste en l'utilisation de triethyl silane et d'acide trifluoro acetique pour la reduction des pyrrolidine dicarboxylates-2,2 initiaux, et en la protection du N des prolines par le t-butoxycarbonyl; les racemiques obtenus sont ensuite dedoubles

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. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.

N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1) is a novel alpha(1) agent having the unique profile of alpha(1A) (rabbit urethra, EC(50) = 0.60 microM) agonism with alpha(1B) (rat spleen, pA(2) = 5.4) and alpha(1D) (rat aorta, pA(2) = 6.2) antagonism. An in vivo dog model showed 1 to be more selective for the urethra over the vasculature than A-61603 (2), ST-1059 (3, the active metabolite of midodrine), and phenylpropanolamine (4).

Compounds of formula (I) are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.

Compounds that are clinically used as hypnotics, sedatives, anxiolytics, and anticonvulsants share a spectrum of related activities that may reflect a common molecular substrate within the brain. The alcohols, benzodiazepines, and barbiturates represent the principal classes of compounds reviewed. Whereas the mode of action of a number of hypnotics, sedatives, and anxiolytics is known, many agents used as anticonvulsant agents act by unknown mechanisms and as a result have considerable side effect liabilities. Newer agents including γ-aminobutyric acid (GABA) modulators, glutamate and N-methyl-d-aspartate acid (NMDA)-receptor antagonists, nonbenzodiazepine ligands for the central benzodiazepine (BZ)receptor, and a variety of miscellaneous agents including CCK-A receptor antagonists (CI-988) and 5HT receptor modulators are also discussed. Keywords: Sedatives; Hydantoin; Anticonvulsants; Hypnotics; Alcohols; Barbiturates; Benzodiazepines; Succinimdes; Anxiolytics