The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with (14)C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney--the target of current drugs--could lead to improved sodium management in renal disease.

UDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 (N‐((S)‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1R,2R)‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose‐limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC‐516, (S)‐N‐(2‐(hydroxyamino)‐1‐(3‐methoxy‐1,1‐dioxidothietan‐3‐yl)‐2‐oxoethyl)‐4‐(6‐hydroxyhexa‐1,3‐diyn‐1‐yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL−1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

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Background: Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with chronic kidney disease (CKD), there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the non-diabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Methods: Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib+enalapril), and untreated controls. Serum creatinine, systolic blood pressure (SBP) and urinary albumin were measured at intervals. Animals were sacrificed at week 12 for histological, biochemical, and molecular analyses. Results: All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8-12 reduced SBP versus controls, decreased albuminuria and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, while selonsertib treatment reduced apoptosis and podocyte loss. RNA-Seq revealed that combined treatment impacted pathways related to extracellular matrix and wound-healing. Conclusions: Selonsertib targets a novel, non-hemodynamic pathway in CKD. Our data suggest that ASK1 inhibition when combined with ACEI has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.

Moreover, ␤-myosin heavy chain (␤-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased ␤-MHC and ANF expression. Although several studies report agerelated declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life. cardiac hypertrophy; isoproterenol IT IS WELL ESTABLISHED THAT older patients, when subjected to increases in sympathetic drive and/or afterload, develop heart failure (HF) more frequently compared with younger populations (21,23,33,36). Additionally, incidences of cardiovascular disease, cardiac hypertrophy, and HF are more prevalent with advancing age (7,8). The aging heart, in both humans and rats, becomes functionally impaired at the level of the organ and the cardiomyocyte (7,21,33). Age-related decreases in the contractile reserve of the heart are associated with left ventricular (LV) hypertrophy, activation of proapoptotic enzymes, and calcium cycling defects within the myocyte (2,9,19,22). The underlying cause of age-related declines in systolic performance are not completely understood but may include the following: a decrease in crucial Ca 2ϩ handling proteins such as sarco(endo)plasmic reticulum Ca 2ϩ -ATPase-2a (SERCA2a), a shift in myosin gene expression that results in higher levels of low-velocity ␤-myosin heavy chain (␤-MHC), or an increase in caspase activity. (1, 7-10, 21, 22, 33). Chronic administration of the nonselective ␤-receptor agonist isoproterenol (ISO) is an experimental model of cardiac hypertrophy that is characterized by decreases in cardiac contractility, disruptions in intracellular Ca 2ϩ handling, and increases in cardiomyocyte apoptosis and necrosis (6, 32, 51). Chronic increases sympathetic activity and the sustained elevation of circulating catecholamines are known to worsen systolic function and to decrease contractile reserve, whereas ␤-receptor antagonism mitigates the progression of clinical HF (31,36).A blunted contractile reserve is indicative of decreased myocardial viability and characteristic of human HF (5, 44). Inotrope-induced increases in [maximum of LV pressure development (ϩdP/dt max )] reflects contractile reserve, and this index is measured to clinically assess a patient's cardiac performance (26,44). Cardiac function can often appear normal until subjected to stresses, such as excessive adrenergic stimulation, which reveal underlying impairments (23, 36). In fact, an ample contractile reserve is predictive of a better prognosis in patients with LV dysfunction at rest (18).Because mature adults may have a diminished capacity to respond to cardiac stress compared with those in the growing phase, and because agi...