(S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor.

A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.

Azetidinones as vasopressin V1a antagonists.

The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.

3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists.

Syntheses and SAR studies of 3,3-bisaryloxindole analogues provided potent mineralocorticoid receptor (MR) antagonists that were selective over other steroid nuclear hormone receptors.

Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure.

We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na(+) channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or beta-adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not beta-adrenergic blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval-mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY-368052. Thus the Na(+) channel enhancer LY-368052 maintains its beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.

Combined inotropic and bradycardic effects of a sodium channel enhancer in conscious dogs with heart failure: a mechanism for improved myocardial efficiency compared with dobutamine.

We compared the cardiac inotropic, chronotropic, and myocardial O(2) consumption (MVO(2)) responses to the sodium (Na(+)) channel enhancer, LY341311 [(S)-4-[3-[[1-(diphenyl-methyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile monohydrate], with the beta-receptor agonist dobutamine in conscious dogs with heart failure. Heart failure was induced in chronically instrumented dogs by right ventricular pacing at 240 beats per minute for 3 to 4 weeks. LY341311 (10-100 microg/kg/min i.v.) dose dependently increased cardiac contractile function as reflected, at the highest dose, by increases in left ventricular dP/dt(max) (55 +/- 7%), and fractional shortening (62 +/- 9%), accompanied by increases in cardiac stroke work (111 +/- 18%) and minute work (34 +/- 10%) and decreases in heart rate (33 +/- 4%). Dobutamine (2-15 microg/kg/min i.v.) increased contractile responses to a similar degree but also increased heart rate (15 +/- 5%) at the highest dose. Complete ganglionic blockade with hexamethonium and atropine or with hexamethonium alone abolished the bradycardic effect but not the inotropic response to LY341311. At similar levels of inotropic response, dobutamine (10 microg/kg/min) increased MVO(2) by 23 +/- 7% (P < 0.05), whereas LY341311 (100 microg/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO(2) was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O(2) utilization in the failing heart while providing inotropic support comparable to a beta-receptor-mediated agonist.

Aldosterone stimulates angiotensin-converting enzyme expression and activity in rat neonatal cardiac myocytes.

BACKGROUND: Members of the nuclear receptor family proteins function as transcription factors upon ligand binding and thereby regulate gene expression in host cells. Aldosterone, the high-affinity endogenous ligand for the mineralocorticoid receptor, induces cardiac hypertrophy and fibrosis in a variety of animal models, but the transcriptional targets for aldosterone in the myocardium are not well-described. METHODS AND RESULTS: Using quantitative reverse transcription-polymerase chain reaction method, we show that in cultured rat neonatal cardiomyocytes, aldosterone stimulates expression of angiotensin converting enzyme (ACE) in a concentration and time-dependent manner. Aldosterone (50 and 100 nM) increased levels of ACE mRNA by 1.8- and 2.2-fold, respectively. Aldosterone-induced ACE gene expression was blocked by spironolactone (1 microM), a mineralocorticoid receptor antagonist. In contrast, the expressions of the type I angiotensin receptor was not induced by aldosterone in either cardiac myocytes or fibroblasts. Consistent with the increased ACE mRNA level, 100 nM aldosterone also induced a 2-fold increase in ACE activity in cardiac myocytes. CONCLUSION: ACE gene expression may be a target for mineralocorticoid receptors in the myocardium, supporting the notion that at least some of the known adverse effects of aldosterone on the myocardium are mediated by increased angiotensin II.

Identification, synthesis and pharmacological activity of moxonidine metabolites.

The metabolism of moxonidine, 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, LY326869, in rats, mice, dogs, and humans has been examined. At least 17 metabolites were identified or tentatively identified in the different species by HPLC, LC/MS and LC/MS/MS. The identities of seven of the major metabolites have been verified by independent synthesis. The metabolites are generally derived from oxidation and conjugation pathways. Oxidation occurred at the imidazolidine ring as well as the methyl at the 2 position of the pyrimidine ring. All seven metabolites were examined in the spontaneously hypertensive rats (3 mg kg(-1), i.v.) for pressure and heart rate. Only one, 2-hydroxymethyl-4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxypyrimidine, exerted a short-lasting decrease in blood pressure, albeit attenuated in magnitude compared to moxonidine.

A sodium channel enhancer, LY341311, increases myocardial contractile performance without increasing heart rate in conscious normal dogs: a comparison with dobutamine.

BACKGROUND: Catecholamines and many inotropic agents increase cardiac contractility but also cause excessive myocardial O2 consumption (MVO2). We determined if the novel Na+ channel enhancer LY341311, which increases myocardial contractility independent of beta receptors, can produce significant cardiac inotropic effects compared with dobutamine but at lower oxygen cost in conscious dogs. METHODS AND RESULTS: Mongrel dogs were chronically instrumented for measurement of arterial pressure, left ventricular (LV) pressure and internal diameter, coronary blood flow, and arterial and coronary sinus O2 content. Both LY341311 and dobutamine produced dose-dependent increases in LV dP/dt, dP/dt/40, fractional shortening, and cardiac stroke work and minute work estimated from the LV pressure-diameter loop. The major difference between LY341311 and dobutamine was an opposing effect on heart rate with LY341311 slightly reducing it but dobutamine markedly increasing it. LY341311 caused a significantly smaller increase in MVO2 than dobutamine (P <.05) and produced similar cardiac inotropic effects, yielding a higher cardiac mechanical efficiency than dobutamine. However, after pacing to match heart rate with dobutamine LY341311 increased MVO2 markedly, approaching the same level as with dobutamine. CONCLUSIONS: The novel Na+ channel enhancer LY341311 caused significant increases in myocardial contractility and contractile performance without increasing heart rate. It had a beneficial energetic effect on the heart with significantly less O2 cost and improved cardiac mechanical efficiency.

Inhibitory Effects of LY301875 on Responses to Angiotensin Peptides in Pulmonary Vascular Bed of the Cat.

The effects of the nonpeptide angiotensin receptor antagonist LY301875 on responses to angiotensin II, angiotensin III, and angiotensin IV were investigated in the pulmonary vascular bed of the intact cat chest. Under conditions of controlled blood flow, injections of the angiotensin peptides into the perfused lobar artery caused dose-related increases in lobar arterial pressure, and LY301875 decreased pressor responses to angiotensin II, angiotensin III, and angiotensin IV. The duration of the blockade was related to the dose of the antagonist, and LY301875 had no significant effect on pressor responses to U-46619, norepinephrine, serotonin or BAY K 8644. LY301875 caused minimal decreases on mean baseline systemic arterial pressures and did not significantly affect lobar arterial pressure in the cat. These results indicate that LY301875 is a potent selective long-acting angiotensin receptor antagonist and suggest that this agent may be useful in the investigation of the role of angiotensin peptides in physiological and pathophysiological processes in the pulmonary vascular bed.