The synthesis and evaluation of indolylureas as PKCa inhibitors Jane F. Djung a , Richard. J. Mears b,⇑ , Christian A. G. N. Montalbetti b , Thomas S. Coulter b , Adam Golebiowski a,  , Andrew N. Carr a , Oliver Barker b , Kenneth D. Greis a,à , Songtao Zhou a,§ , Elizabeth Dolan a , Gregory F. Davis a a Procter & Gamble Pharmaceuticals Inc., Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040-9462, USA b Evotec, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK article info Article history: Received 16 January 2011 Revised 17 February 2011 Accepted 21 February 2011 Available online 26 February 2011 Keywords: Protein kinase C alpha Kinase inhibitor Heart disease Indolylurea abstract PKCa and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCa, but not PKA, are potential therapeutic targets for the treat- ment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCa with significant selectivity over PKA has been identified. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Heart failure is one of the leading causes 1 of morbidity and mor- tality in developed nations. In the US, 5 million 2 people suffer from heart disease with over 700,000 new cases presenting every year. Over 1 million hospitalizations/year result from this condition in the US, with an estimated cost of $30–40 billion/annum. 2b,c,3 The mechanism of heart failure progression involves multiple causes, including hypertension, atherosclerosis and a variety of risk factors which lead to cardiac hypertrophy, impaired calcium handling by cardiomyocytes and ultimately heart failure. 4 While this disease is well characterised 5 and several therapies are available for treat- ment, patients’ outcomes remain poor with a five-year mortality rate of approximately 50%. A hallmark of heart failure is depressed cardiac function due to impaired calcium handling within the cells of the heart or cardio- myocytes. 6 The goal of several experimental therapies is to im- prove calcium handling and thus, restore the heart’s function (inotropic/lusitropic therapy 7 ) which would be beneficial in patients with emergent or acute heart failure. Recent evidence has revealed that PKCa and PKA play crucial, but opposing roles in the regulation of calcium handling within myocytes. 8a–d The function of PKCa in cardiomyocytes appears to be to reduce cal- cium cycling capacity within the myocyte, leading to a reduction in cell function (impaired contraction and relaxation), in part via dephosphorylation of phospholamban 8a and inhibition of the sar- coplasmic/endoplasmic reticulum Ca 2+ ATPase (SERCA) or SR Ca 2+ pump. This decrease in SERCA activity prolongs the time for cyto- solic calcium removal (decreased cardiac relaxation time) and may lead to elevated cytosolic calcium concentrations (increased dia- stolic tension). In turn, as less cytosolic calcium is sequestered by SERCA, less calcium is available for subsequent contractions, diminishing contractile force. In the chronic setting, there is evi- dence that PKCa may be a key intracellular signalling kinase involved in activating signalling pathways which promote cardio- myocyte hypertrophy. 9 These data supported by reports 10 demon- strating that PKCa activity/expression is increased in the human failing heart, provide evidence that inhibition of this kinase may provide therapeutic benefit to heart failure patients. A number of PKC inhibitors have been prepared 11 several of which have progressed to the clinical trial stage 12a–d for the treat- ment of various disorders. Among them, the bis-indolylmaleimides A (Ruboxistaurin [LY333531], macular edema, diabetic kidney disease, PKCb), B (Enzastaurin [LY317615], malignant glioma, pancreatic, colorectal and non-small cell lung cancer, PKCb), C (Midostaurin [PKC412], acute myeloid leukaemia, aggressive systemic mastocytosis and mast cell leukaemia, PKCa, b, c) and 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.02.036 ⇑ Corresponding author. Tel.: +44 0 1235 861561; fax: +44 0 1235 838931. E-mail address: richard.mears@evotec.com (Richard. J. Mears).   Present address: The Institute for Pharmaceutical Discovery, 23 Business Park Drive, Brandford, CT 06405, USA. à Present address: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA. § Present address: 1 Procter & Gamble Plz, Cincinnati, OH 45202-3393, USA. Bioorganic & Medicinal Chemistry 19 (2011) 2742–2750 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc