Synthesis and evaluation of diphenylphosphinic amides and diphenylphosphine oxides as inhibitors of Kv1.5 Roine I. Olsson a,⇑ , Ingemar Jacobson b , Jonas Boström b , Tomas Fex b , Annika Björe b , Christina Olsson b , Johan Sundell b , Ulrik Gran b , Anna Öhrn b , Andreas Nordin b , Jonna Gyll b , Maria Thorstensson b , Ahlke Hayen b , Karolina Aplander b , Olle Hidestål b , Fanyi Jiang a , Gunilla Linhardt b , Elin Forsström b , Teresa Collins b , Monika Sundqvist b , Emma Lindhardt b , Annika Åstrand a , Boel Löfberg b a Respiratory & Inflammation iMed, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden b Cardiovascular & Gastrointestinal iMed, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden article info Article history: Received 22 October 2012 Revised 23 November 2012 Accepted 25 November 2012 Available online 3 December 2012 Keywords: Atrial fibrillation Kv1.5 IKs Diphenylphosphinic amides Diphenylphosphine oxides abstract Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibi- tors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure– activity relationships are discussed and several compounds with Kv1.5 IC 50 values of <0.5 lM were dis- covered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included. Ó 2012 Elsevier Ltd. All rights reserved. Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, often giving symptoms that reduce health re- lated quality of life, causing a considerable burden in hospitaliza- tion and increasing the risk of stroke and other cardiovascular morbidities and mortality. 1 AF is frequently associated with other cardiovascular disease such as hypertension, coronary artery dis- ease, valvular heart disease and congestive heart failure. With con- tinuous growth of the elderly population, AF can be expected to have an increasing impact on managed care and public health. However, so far no atrial specific drug treatment exists and cur- rently used antiarrhythmic drugs target ion channels that are pres- ent both in cardiac atria and ventricles. 2 The potassium ion channel Kv1.5, encoded by the gene KCNA5, has been in focus as a target for pharmacological treatment of AF during the past decade and numerous reports of the design and synthesis of compounds targeting Kv1.5 have emerged. 3–7 Kv1.5 channels conduct the ultra rapidly activating delayed rectifier K + current, IKur, a current predominantly expressed in human cardiac atria and block of these channels has the potential to selectively af- fect the atrial myocytes. In the present paper we describe the discovery, synthesis and evaluation of novel phosphorous compounds as inhibitors of Kv1.5. There were several underlying motives for exploiting phos- phorous atoms in compound design against this target. In the first instance, phosphorous is underused compared to carbon despite the fact that the phosphorous atom has similar properties as the carbon atom. 8 Secondly, a series of diphenylphosphine oxides, like DPO-1 (Fig. 1), has been identified as Kv1.5 blockers 9 and the series has also been used as a starting point for lead identification. 10 Fi- nally, AstraZeneca has previous experience of phosphorous com- pounds in clinical development. 11 A substructure search of the AstraZeneca corporate collection provided a few hundred phosphorus containing compounds. From this list of compounds, diphenylphosphinic amide A (Fig. 1) over- laid well with the previously identified potent Kv1.5 blocker B 12 using shape-matching technology 13 (Fig. 2). The ion channel-blocking potency on the Kv1.5 channel was as- sessed in a CHO cell line stably expressing the human cardiac ion channel Kv1.5. Similarly, the potency at blocking hERG and KvLQT1/minK channels, was assessed. hERG underlies the cardiac current IKr and KvLQT1/minK the cardiac current IKs, both affect- ing the cardiac ventricular repolarization. Electrophysiological studies were performed using a high throughput planar patch clamp assay and standard extra- and intracellular solutions. 14,15 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.11.098 ⇑ Corresponding author. E-mail address: Roine.i.olsson@astrazeneca.com (R.I. Olsson). Bioorganic & Medicinal Chemistry Letters 23 (2013) 706–710 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl