Current Medicinal Chemistry, 2007, 14, 279-287 279 Diltiazem Analogues: The Last Ten Years on Structure Activity Relationships Roberta Budriesi *,1 , Barbara Cosimelli 2 , Pierfranco Ioan 1 , Emanuele Carosati 3 , Maria P. Ugenti 1 and Rraffaella Spisani 4 1 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italia 2 Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli “Federico II”, Via Montesano 49, 80131 Napoli, Italia 3 Dipartimento di Chimica, Università di Perugia, via Elce di Sotto 10, 06123 Perugia, Italia 4 Dipartimento di Chimica Organica “A. Mangini”, Università degli Studi di Bologna, Via S. Giacomo 11, 40126 Bologna, Italia Abstract: Cardiovascular diseases as hypertension, angina and/or supraventricular arrhythmias are among the most important death causes in the world. For the treatment of heart pathologies, calcium channel entry blockers are very important drugs, owing to their therapeutic versatility. Although few calcium antagonists described until today are structurally related to diltiazem and to the benzothiazepine class, the still high pharmaceutical interest on diltiazem analogues justifies this review. Diltiazem and its first analogues developed in the early ‘70s became popular in the ‘80s, and were pharmacologically characterized for a long time. It is in the ‘90s that several research groups carried out structural variations identifying novel scaffolds for diltiazem-related compounds, with significant calcium antagonist behaviour. Recently, a series of thiazino-oxadiazolone derivatives were identified as potent and selective antagonists for calcium influx into cardiac cells, and they were subsequently used to search for novel chemotypes by means of virtual screening techniques. The resulting hits could open interesting perspectives for the development of drugs to treat cardiovascular diseases. In the present review, an updated collection of diltiazem analogues is reported over the last ten years. The chemical structure and the structure activity relationships will be given, with additional mention to the potential therapeutic applications. 1. INTRODUCTION heterogeneous group of drugs approved for the treatment of hypertension and heart diseases in the 1980s [3]. The increased knowledge of biological mechanisms found calcium ions an essential element for the regulation of a large variety of cellular functions such as contraction, secretion, neurotransmission, and gene expression. In particular, Ca 2+ plays a crucial role in the excitation- contraction coupling process of muscle cells [1]. The German physiologist Albrecht Fleckenstein first reported on a series of chemically unrelated drugs that mimicked the cardiac effects of simple Ca 2+ withdrawal: these compounds were called calcium antagonists [2]. Their pharmacological property regards the modulation of the influx of calcium ions through voltage-gated L-type calcium channels in the cellular membrane. CEBs show tissue specificity both in vitro and in vivo. Different reasons could explain this selectivity, including: classes and subclasses of calcium channels, tissue distribution of drugs, and different state and voltage- dependent interactions on the basis of the tissues. At present, the recombinant cardiac and smooth muscle L-type calcium channels (Ca V 1.2a and Ca V 1.2b, respectively) seem to be one of the most probable cause of DHPs tissue selectivity. Of course, more potent and selective compounds must be discovered to elucidate this point, and this could pave the way for new targets in cardiovascular therapy [4]. 1.1. Voltage-Gated Calcium Channels At present, 1,4-dihydropyridines (DHPs, nifedipine 1, isradipine 2), phenylalkylamines (PAAs, verapamil 3), and benzothiazepines (BTZs, diltiazem 4) (Fig. 1) are the calcium entry blockers (CEBs) in clinical use. They belong to a structurally, pharmacologically, and therapeutically The gene superfamily of transmembrane ion channel proteins includes voltage-gated Ca 2+ , Na + and K + channels [5]. They all possess stereoselective drug binding domains with well defined structure-activity relationships, and they are in equilibrium between three different transition states: resting (closed), activated (open), and inactivated [6]. *Address correspondence to this author at the Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italia; Tel.: +39-051-2099737, Fax: +39-051-2099721; E-mail: roberta.budriesi@unibo.it Calcium channels are classified into several types according to the high/low voltage of the currents recorded in 0929-8673/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.