Discovery and Development of Calcium Channel Blockers

Abstract

In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan) and Heibrunn (USA) experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB) of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are important factors of their action. The high sensitivity of hypertensive animals is explained by the partial depolarization of their arteries. It is noted that they are arteriolar dilators and that they cannot be simply considered as vasodilators. The second part of this report provides key information about clinical usefulness of CCBs. A section is devoted to the controversy on their safety closed by the Allhat trial (2002). Sections are dedicated to their effect in cardiac ischemia, in cardiac arrhythmias, in atherosclerosis, in hypertension, and its complications. CCBs appear as the most commonly used for the treatment of cardiovascular diseases. As far as hypertension is concerned, globally the prevalence in adults aged 25 years and over was around 40% in 2008. Usefulness of CCBs is discussed on the basis of large clinical trials. At therapeutic dosage, they reduce the elevated blood pressure of hypertensive patients but don't change blood pressure of normotensive subjects, as was observed in animals. Those active on both L- and T-type channels are efficient in nephropat...

First‐in‐man study of ACT‐709478, a novel selective triple T‐type calcium channel blocker

“…T‐type Ca 2+ channels are known to be expressed in heart cells and kidney, playing an important role in the pacemaker current and in the regulation of aldosterone, respectively . Moreover, L‐/T‐type Ca 2+ channel blockers are used in the treatment of hypertension and other cardiac disorders . In this study, no clinically relevant treatment‐emergent findings in vital signs, ECGs, or heart rate telemetry were observed.…”

Functional mechanism of tracheal relaxation, antiasthmatic, and toxicological studies of 6‐hydroxyflavone

“…ASM contraction is dependent on the phosphorylation of the regulatory myosin light‐chain mediated by myosin light‐chain kinase, which is in turn activated by the binding of calmodulin and calcium (Chen & Sanderson, ; Pfitzer, ). Hence, an increase of intracellular calcium concentration ([Ca 2+ ]i) induces the contraction of ASM; in this regard, the flavonoid relaxed the contraction induced by KCl 80 mM (Figure a), similar to Nifedipine (an L‐type calcium channel blocker), employed as positive control; while the CaCl 2 ‐induced contraction was significantly reduced by the 6‐HOF (Figure b), suggesting that the flavonoid acts as a calcium channel blocker (Godfraind, ). The contraction of smooth muscle induced by high K + is dependent on the entry of Ca 2+ into the cells through voltage‐operated calcium channel (VOC) cell‐membrane depolarization, while inhibition of high K + ‐induced contraction is because of the result of blocked Ca 2+ entry through these VOC (Ghayur, Gilani, Khan, Amor, & Choudhary, ; Godfraind, ; Yagi, Kuwahara, & Tsubone, ).…”

“…Hence, an increase of intracellular calcium concentration ([Ca 2+ ]i) induces the contraction of ASM; in this regard, the flavonoid relaxed the contraction induced by KCl 80 mM (Figure a), similar to Nifedipine (an L‐type calcium channel blocker), employed as positive control; while the CaCl 2 ‐induced contraction was significantly reduced by the 6‐HOF (Figure b), suggesting that the flavonoid acts as a calcium channel blocker (Godfraind, ). The contraction of smooth muscle induced by high K + is dependent on the entry of Ca 2+ into the cells through voltage‐operated calcium channel (VOC) cell‐membrane depolarization, while inhibition of high K + ‐induced contraction is because of the result of blocked Ca 2+ entry through these VOC (Ghayur, Gilani, Khan, Amor, & Choudhary, ; Godfraind, ; Yagi, Kuwahara, & Tsubone, ). Morel and Godfraind described that, in the presence of dihydropyridines, KCl‐dependent contraction is lowered as a function of the concentration of the blocker and duration of the depolarization, implying that membrane potential is involved in dihydropyridine action, such as that revealed by Nifedipine (Figure a) (Morel & Godfraind, ).…”

Deciphering Structure–Activity Relationships in a Series of 2,2‐Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants

“…The biological effects of the selected dimethylchromans (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), 29 and its enantiomers (+)-and (À)-29,a nd reference compounds (AE)-cromakalim and diazoxide on glucose-induced insulin release from rat pancreatic isletsa nd on the contractile activity of K + -depolarizedr at aorta rings are reported in Ta ble 1.…”

“…From the core structure 4-amino-2,2-dimethylchroman, ap rogressive increasei nt he steric hindrance of the chemicalf unctionalities introduced at the 4-position (amino, formamido, acetamido, arylureido/thioureido) and at the 6-position (amino, formamido, acetamido, alkoxycarbonylamino) led to ap rogressive magnification of the inhibitory effect on the insulin release process and, to al esser extent,o ft he vasorelaxanta ctivity.M oreover,t he dextrorotatory enantiomer of 2,2-dimethylchroman compound 29 was more potent than its levorotatory counterpart for inhibiting the insulin secretory process.A dditionalp harmacological investigations suggested, however, that the myorelaxant activity of 11 and 15 resulted from ad irect Ca 2 + entry blockade. [17] Within this context, we previously described an ovel series of cromakalim analogues. Chemical structureso fc romakalim (1;ast he most active enantiomer,l evcromakalim) and previously described 2,2-dimethylchromans (2)(3)(4)(5)(6)(7)(8) that act as inhibitors of insulinrelease and/or smooth musclerelaxants.…”