Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.

We have identified a small molecule inhibitor, MYK0000461, of the cardiac myosin ATPase. This agent was characterized in steady state and transient kinetic assays to understand its mechanism of action. MYK0000461 decreases the steady-state rate of the ATPase activity of purified bovine β-cardiac myosin subfragment-1 (S1) as well as that of bovine cardiac myofibrils, wild type and the mutant R453C of recombinant human β-cardiac myosin S1. We also find that MYK0000461 inhibits cardiac myosin selectively as compared to systems containing rabbit skeletal or chicken smooth muscle myosins Analysis of the individual steps of the chemo-mechanical cycle of cardiac myosin suggests that MYK0000461 exerts its effect by inhibiting the actin-stimulated release of phosphate, presumably by stabilizing the detached state of cardiac myosin prior to the release of phosphate. We find no evidence to suggest that MYK000461 inhibits cardiac myosin in a strongly bound state and no other steps in the chemo-mechanical cycle are affected by MYK0000461. Thus, the enzymatic step governing the weak to strong transition of S1 binding to actin is inhibited without affecting the release from the strongly bound states. This decrease in the rate of transition from the weak to strongly bound state should decrease force production and may underlie its ability to decrease cardiac contractility in cellular and in vivo models of cardiac function. An agent such as MYK0000461 could potentially be used to treat cardiac disorders that stem from hyper contractility such as the genetic hypertrophic cardiomyopathies (HCM). By decreasing the net force of contraction and restoring it back to normal level could potentially be useful in treating patients that suffer from this disease.

Genetic hypertrophic cardiomyopathy (HCM) results from mutations in the cardiac sarcomere, including β-cardiac myosin, with HCM afflicting about 1 out of every 500 people in the United States. HCM is characterized by hyper-contractility and myocyte hypertrophy. Current agents used to treat HCM include β-blockers and Ca2+ channel blockers to decrease the hyper-contractility and improve cardiac relaxation. A novel and more direct approach to decreasing hyper-contractility and improving diastolic relaxation in HCM patients is by modulating β-cardiac myosin to produce less force. We believe modulation at the sarcomere level provides a focused strategy while lowering the potential for adverse drug events. In this study we examined the effects of MYK0000461, a cardiac myosin selective inhibitor, on adult rat cardiomyocytes to fully understand the mechanism of action on excitation-contraction (E-C) coupling. Cellular contractility was assessed using edge detection and the calcium transient was measured using fura-2 loaded myocytes. MYK0000461 decreased contractility in a dose dependent manner with an IC50 of 250nM without altering the calcium transient. This inhibitory effect can be reversed by stimulation of the β-adrenergic pathway with the known agonist isoproterenol. We hypothesize that modulation of mutant β-cardiac myosin activity with a small molecule agent such as MYK0000461 could potentially treat disorders resulting from hyper-contractility such as HCM.

La presente invention concerne des composes qui sont des modulateurs de la synthese d'acides gras. Lesdits composes peuvent etre utilises pour traiter des troubles caracterises par un dereglement de la fonction de l'acide gras synthase, par la modulation de la fonction et/ou de la voie de l'acide gras synthase. L'invention concerne egalement des methodes de traitement de tels troubles, notamment d'infections virales, telles que l'hepatite C, le cancer et des troubles metaboliques.

Potent imidazopyridine-based inhibitors of fatty acid synthase (FASN) are described. The compounds are shown to have antiviral (HCV replicon) activities that track with their biochemical activities. The most potent analogue (compound 19) also inhibits rat FASN and inhibits de novo palmitate synthesis in vitro (cell-based) as well as in vivo.

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

This letter describes the structure-activity relationship (SAR) of the 'right-wing' alpha-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing alpha-amino acids have been identified as replacements of the 'right-wing' (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved. (C) 2010 Elsevier Ltd. All rights reserved.

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.