Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication.

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Mannich reactions with chiral silicon Lewis acid-activated acylhydrazones and α-aryl silyl ketene acetals and α-aryl, α-alkyl silyl ketene imines proceed efficiently and with good to excellent levels of both diastereoselectivity and enantioselectivity. The reactions provide access to α-aryl,β-hydrazido esters and α-aryl,α-alkyl,β-hydrazido nitriles, which are valuable analogs of β-amino acids.The Mannich reaction -broadly defined as the addition of an enol, enolate, or enolate equivalent to an imine -provides access to β-amino acids and related structures, and in recent years has been the subject of an extraordinary amount of effort directed towards the development of efficient and highly enantioselective variants. 1 While impressive successes have been recorded using several different approaches, the substrate scope remains limited in notable ways. For example, there are relatively few reports that describe highly diastereoselective and/or enantioselective Mannich reactions of α-aryl substituted enolates (or enolate equivalents). 2 This relative paucity of general methods is particularly noteworthy as an examination of the literature reveals many examples of bioactive compounds and natural products with an α-aryl,β-aminocarboxyl substructure (Figure 1). This subset of Mannich reactions is thus one of fundamental synthetic importance for which there are few practical, general, and highly enantioselective solutions. Herein we report highly enantioselective Mannich reactions with α-aryl silyl ketene acetals and with α-aryl,α-alkyl silyl ketene imines that allow direct access to structures such as those depicted in Figure 1 using convenient, inexpensive, and scalable procedures.We recently reported neo-pentoxychlorosilane 1 and its use in highly enantioselective Mannich reactions of aliphatic ketone-derived acylhydrazones with silyl ketene acetal (SKA) 2 (Scheme 1), 3,4 and this seemed a reasonable starting point for the present investigation. Indeed, it was quickly found that SKA 3 (prepared and employed as 13:1 Z:E mixture) reacts smoothly with the silane 1/hydrazone 4a complex to give syn-Mannich product 5a. Optimization was straightforward and by performing the reaction in CH 2 Cl 2 at leighton@chem.columbia.edu. Supporting Information Available: Experimental procedures, characterization data, and stereochemical proofs. This material is available free of charge via the Internet at http://pubs.acs.org. Summarized in Table 1 is a brief survey of the scope of the reaction with respect to the hydrazone substrate. Optimization focused on the nature of the group (R′) on the hydrazone as we have found that this can have a significant effect on reaction performance. The use of both aromatic and aliphatic aldehyde-derived hydrazones resulted in excellent levels of enantioselectivity (entries 1-4), albeit with only moderate diastereoselectivity for unhindered aliphatic substrates (entries 2 and 3). As shown in entry 5, however, this moderate diastereoselectivity may be significantly improved simply by performing ...

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Late sodium current (late I) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

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The first general method for the highly enantioselective Mannich reaction of aliphatic ketimines is reported. A new, second generation chiral silane Lewis acid has been developed that promotes the reaction between ketone-derived hydrazones and silyl ketene acetals, providing the beta,beta-disubstituted beta-amino esters with good enantioselectivity even for the hydrazone derived from 2-butanone (methyl vs ethyl, 91% ee). Several examples are provided, including a reaction with a substituted (propanoate-derived) silyl ketene acetal.