Recent patents on calcium channel blockers: emphasis on CNS diseases

Abstract

Collections of compounds are generally screened in cell lines expressing a given subtype of VACCs. IC50 to block such channels are often, but not always, provided. In few instances, compounds exhibiting the highest potency in in vitro experiments are also tested in animal models of pain, behavior, epilepsy or Alzheimer's disease. Attempts to develop selectivity for a given VACC subtype with non-peptidic organic ligands have so far failed. Due to their wide tissue expression, such selectivity is crucial for minimizing possible side effects. However, the few data reported by patents does not allow prediction of selectivity of the new compounds in many cases.

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

“…To finish up, we hypothesize that compound 23 is an eligible lead compound to further investigate its pharmacological activities in preclinical models of AD, as it demonstrated significant activity over VCGG and Ser/Thr phosphatases, accompanied by a wide-spectrum neuroprotective profile. The fact that compound 23 exerts Ca 2+ blockade preferentially through non-L type VGCC is in agreement to the rising interest of developing both N-and P/Q type VGCC blockers for dementia, 68,84 what supposes a breakthrough in the study of Ca 2+ antagonists for central nervous system diseases because they could bypass the cardiovascular side effects resulting from peripheral L-type channel blockade, [25][26] Hence, the derivative 1-benzyl-5-methyl-3-(piperidin-1-ylmethyl)-1H-indole (compound 23, which we have named ITH12657) features an innovative multitarget-based mechanism of action, aiming neuronal Ca 2+ control and Ser/Thr phosphatase activity. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 aluminum oxide (Brockmann I) columns were used in a Biotage chromatographic station.…”

Review: Cav2.3 R-type Voltage-Gated Ca2+ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity

“…Thus, caution has to be exercised when interpreting SNX-482 antagonistic effects on cells and neural circuits where these channels are actually expressed. Ca v 2.3 blocking effects were also reported for DW 13.3, the Phoneutria (Ctenus) nigriventer (Brazil armed spider) toxin ω-ctenitoxin-Pn2a including ω-PnTx3-3, ω-PnTx3-6 and ω-phonetoxin IIA [20]. In addition, Ca v 2.3 Ca 2+ channels exhibit high sensitivity to divalent heavy metal ion such as Ni 2+ (IC 50 = 27 μM), a property that they share with Ca v 3.2 Ca 2+ T-type channels (IC 50 = 5-10 μm [130],).…”

“…Recently, ω-TRTX-Cc1a, derived from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus ), turned out to be a potent and selective blocker of Ca v 1.2 and Ca v 1.3 Ca 2+ channels [19]. Experimental activators of L-type channels include BayK8644, FPL64176, PCA50941 and SZ(+)-(S)-202-791, none of which is however used in clinical application settings [20]. …”

“…Other Ca v 2.1 blockers include ω-agatoxin IIIA, ω-agatoxin IVB, peptide toxins from the venom of the marine snail Conus geographus , i.e . ω-conotoxin MVIID, ω-conotoxin CVIB, ω-conotoxin CVIC, the spider toxin ω-phonetoxin IIA derived from Phoneutria nigriventer , DW13.3 extracted from the venom of the spider Filistata hibernalis and the scorpion venom toxin Kurtoxin [20, 22-24]. Though widely used in basic science, none of these blockers has reached clinical application so far.…”

“…Arranz-Tagarro et al . [20] provided a summary of 23 patents in the period 2011-2013 claiming selectivity of newly synthesized compounds for HVA L- and N-type and LVA T-type Ca 2+ channels. It’s noteworthy that indications of L-type blocker patents are mostly related to treatment of Parkinson’s disease but also cardiovascular and neurodegenerative diseases.…”