FENDILINE HYDROCHLORIDE Property

Melting point:

204-205℃

solubility 

Soluble in ethanol.

form 

Powder

color 

White to off-white

Safety

Hazard Codes 

Xn

Risk Statements 

22

Safety Statements 

36

WGK Germany 

3

RTECS 

DP4790000

Toxicity

LD50 in mice (mg/kg): 14.5 i.v.; 950 orally (Harsányi)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P330Rinse mouth.

FENDILINE HYDROCHLORIDE Chemical Properties,Usage,Production

Originator

Sensit,Thiemann,W. Germany,1974

Uses

Antianginal;Ca++ channel activator

Uses

Fendiline is an α2-adrenergic receptor antagonist (Kd = 2.6 μM) and an L-type calcium channel blocker (IC50 = 17 μM) well-known for its coronary vasodilator effects. Fendiline has recently been reported to inhibit K-Ras plasma membrane localization (IC50 = 9.64 μM), which prevents K-Ras signal transduction and blocks the proliferation of K-Ras-transformed tumor cells.

Uses

Fendiline hydrochloride is used as a calcium channel blocker.

Manufacturing Process

21.13 grams of γ,γ-diphenyl-propylamine and 12.01 grams of acetophenone are hydrogenated in 200 ml of methanol at 55°C and a pressure of 10 atmospheres in the presence of palladium charcoal. On filtration of the catalyst the solution is concentrated and the remainder is distilled in vacuo at a pressure of 0.3 Hg mm. The main distillate is collected at 206° to 210°C. 25.38 grams of N-[1'-phenylethyl-(1')]-1,1-diphenyl-propyl-(3)-amine are obtained.
The product is dissolved in 134 ml of 96% ethanol whereupon 26.8 ml of concentrated hydrochloric acid and 201 ml of water are added while cooling with ice-water. The precipitate is filtered off and dried in vacuo at 100°C. 22.98 grams of N-[1'-phenylethyl)-(1')]-1,1-diphenyl-propyl-(3)-amine hydrochloride are obtained. MP 200° to 201°C. On recrystallization from 285 ml of a 2:1 mixture of water and 96% ethanol the melting point remains unchanged.

Therapeutic Function

Coronary vasodilator

Biological Activity

fendiline is an α2-adrenergic receptor antagonist and l-type calcium channel blocker [1,2].the α2 adrenergic receptor is a g protein-coupled receptor (gpcr). until now, three different α2-receptor subtypes have been identified: α2a, α2b, and α2c. the α2-adrenergic receptor exists in vascular prejunctional terminals and inhibits the release of norepinephrine in a form of negative feedback. the α2 adrenergic receptor agonists produce diverse responses, including analgesia, sedation, anxiolysis, and sympatholysis [3]. l-type calcium channels are responsible for the excitation-contraction coupling of skeletal, cardiac muscle, smooth, and for aldosterone secretion in endocrine cells of the adrenal cortex [4].fendiline inhibited the activity of l-type ca2+ channel blocker with the ic50 value of 17 μm [1]. fendiline inhibited the activity of α2-adrenergic receptor with the kd of 2.6 μm [2]. fendiline significantly reduced nanoclustering of k-ras and redistributed k-ras from the plasma membrane to the endoplasmic reticulum (er), golgi apparatus, endosomes, and cytosol. fendiline significantly inhibited signaling downstream of constitutively active k-ras and endogenous k-ras signaling in cells transformed by oncogenic h-ras. fendiline blocked the proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant k-ras [5]. fendiline inhibited k-ras plasma membrane localization with an ic50 of 9.64 μm [5]. fendiline is an anti-anginal agent for the treatment of coronary heart disease. the anti-anginal and anti-ischaemic efficacy of fendiline has been proven in several placebo-controlled, double-blind trials [6].

storage

Store at +4°C

References

[1] tripathi, o. ,schreibayer, w., and tritthart, h.a. fendiline inhibits l-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study. british journal of pharmacology 108(4), 865-869 (1993).
[2] motulsky, h. j.,snavely, m.d.,hughes, r.j., et al. interaction of verapamil and other calcium channel blockers with α1- and α2-adrenergic receptors. circulation research 52(2), 226-231 (1983).
[3] kamibayashi t, maze m. clinical uses of α2-adrenergic agonists[j]. the journal of the american society of anesthesiologists, 2000, 93(5): 1345-1349.
[4] lipscombe d. l-type calcium channels[j]. 2002.
[5] van der hoeven d, cho k, ma x, et al. fendiline inhibits k-ras plasma membrane localization and blocks k-ras signal transmission[j]. molecular and cellular biology, 2013, 33(2): 237-251.
[6] bayer r, mannhold r. fendiline: a review of its basic pharmacological and clinical properties[j]. pharmatherapeutica, 1986, 5(2): 103-136.