AIMS:Despite improvements in patient identification and management, heart failure (HF) remains a major public health burden and an important clinical challenge. A variety of animal and human studies have provided evidence suggesting a central role of calcium/calmodulin-dependent protein kinase II (CaMKII) in the development of pathological cardiac remodelling and HF. Here, we describe a new potent, selective, and orally available CaMKII inhibitor.METHODS AND RESULTS:Chemical optimization led to the identification of RA306 as a selective CaMKII inhibitor. This compound was found potent on the cardiac CaMKII isoforms delta and gamma (IC50 in the 10 nM range), with pharmacokinetic properties allowing oral administration in animal models of HF. RA306 was administered to diseased mice carrying a mutation in alpha-actin that is responsible for dilated cardiomyopathy (DCM) in humans. In two separate studies, RA306 was orally administered at 30 mg/kg either for 2 weeks (twice a day) or for 2 months (once a day). Echocardiography monitoring showed that RA306 significantly improved cardiac function (ejection fraction and cardiac output) as compared to vehicle. These disease modifying effects of RA306 were associated with inhibition of cardiac phosphorylation of phospholamban (PLN) at threonine-17, indicating reduced cardiac CaMKII activity.CONCLUSION:This work supports the feasibility of identifying potent orally available CaMKII inhibitors suitable for clinical use to treat heart disease.

Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.

Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues.

A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11β-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11β-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.

Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.