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Efonidipine, エホニジピン



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Efonidipine structure.svg

ChemSpider 2D Image | Efonidipine | C34H38N3O7P



  • Molecular FormulaC34H38N3O7P
  • Average mass631.655 Da
  • エホニジピン
  • CAS 111011-63-3; FREE FORM
Image result for Efonidipine
Molecular Formula: C36H45ClN3O8P
Molecular Weight: 714.193 g/mol

LD50:> 5 g/kg (R, p.o.)

  • Synonyms:NZ-105
  • ATC:C08CA
Efonidipine hydrochloride monoethanolate  111011-76-8 [RN],エホニジピン塩酸塩エタノール付加物
CAS 111011-63-3; FREE FORM
2-(N-Benzylanilino)ethyl (±)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-5-phosphononicotinate Cyclic 2,2-Dimethyltrimethylene Ester
2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate
2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
3-Pyridinecarboxylic acid, 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 2-[phenyl(phenylmethyl)amino]ethyl ester
5-(5,5-Dimethyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic Acid 2-[Phenyl(phenylmethyl)amino]ethyl Ester P-Oxide
Landel [Trade name]
2-(N-benzylanilino)ethyl 5-(5,5-dimethyl-2-oxo-1,3,2$l^{5}-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate

Efonidipine Hydrochloride Ethanolate Bulk & Tablets 10 mg/20mg/40mg, 

Indicated for the management of
• Hypertension
• Renal parenchymal hypertension
• Angina
CDSCO approved INDIA 28.08.2017 
Launched – 1994, Shionogi Zeria
Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel. The drug blocks both T-type and L-type calcium channels [A7844, A32001]. It has also been studied in atherosclerosis and acute renal failure [A32001]. This drug is also known as NZ-105, and several studies have been done on its pharmacokinetics in animals [L1456].

Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel (ランデル). The drug blocks both T-type and L-type calcium channels.[1] Drug Controller General of India (DCGI) granted approval to M/s. Zuventus pharma Ltd for marketing efonidipine under brand name Efnocar in India .[2]

Structure Activity Relationship

Efonidipine is a dual Calcium Channel Blocker (L & T-type). It has a unique chemical structure. The phosphonate moiety (Figure 1) at the C5 position of the dihydropyridine ring is considered to be important for the characteristic pharmacological profile of the drug. (figure-1)

Figure-1:Efonidipine: Chemical Structure

Mechanism of action

Efonidipine, a new generation dihydropyridine (DHP) calcium channel blocker, inhibits both L-type and T-type calcium channels.[1]


  • Efonidipine exhibits antihypertensive effect through vasodilatation by blocking L-type and T-type calcium channels.[1]
  • Efonidipine has a negative chronotropic effect. Working on sino atrial node cells by inhibiting T-type calcium channel activation, Efonidipine prolongs the late phase-4 depolarization of the sino atrial node action potential and suppresses an elevated HR. The negative chronotropic effect of Efonidipine decreases heart rate, myocardial oxygen demand and increases coronary blood flow.[3]
  • Efonidipine increases coronary blood flow by blocking L & T-type calcium channels and attenuates myocardial ischaemia.[4]
  • By reducing synthesis and secretion of aldosterone, Efonidipine prevents hypertrophy and remodeling of cardiac myocytes.[5]
  • Efonidipine increases glomerular filtration rate without increasing intra-glomerular pressure and filtration fraction. This prevents hypertension induced renal damage.[6]
  • Efonidipine prevents Rho-kinase and NFB induced renal parenchymal fibrosis and provides long term renal protection.[7][8]
  • Efonidipine suppresses renin secretion from the juxta glomerular apparatus in the kidneys.[9]
  • Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Aldosterone induced renal parenchymal fibrosis is suppressed by Efonidipine.[5]
  • Efonidipine prevents NFB induced hypertrophy and inflammation in the renal vasculature and protects the kidneys.[7]
  • Efonidipine protects against endothelial dysfunction due to its anti-oxidant activity and by restoring NO bioavailability.[10][11]
  • Efonidipine has anti-atherogenic activity and protects the blood vessels from atherosclerosis.[12]
  • Efonidipine lowers blood pressure in cerebral resistance vessels and prevents hypertension induced brain damage.[4]



Peak plasma concentration is achieved in about 1.5 to 3.67 hours after administration. Half life is approximately 4 hours. The pharmacokinetic parameters of Efonidipine are depicted in Table-1.

Table 1: PK Parameters in Adult Healthy Male Subjects

Variable Efonidipine
Mean Range
Cmax(ng/ml) 36.25 9.66-66.91
Tmax (hour) 2.59 1.50-3.67
T1/2 (hour) 4.18 2.15-6.85

*Data on file

Long Duration of Action

Efonidipine has a slow onset and a long duration of action. This unique characteristic of Efonidipine is because of the following reasons:[13]

  1. High lipophilicity of Efonidipine allows it to enter the phospholipid rich cell membrane and access the dihydropyridine binding site of the Ca2+ channels.
  2. Tight binding to the dihydropyridine receptors.
  3. The dissociation constant of Efonidipine from dihydropyridine receptors is very low (0.0042/min/nM), signifying very slow dissociation from the receptors. This explains the long duration of action of Efonidipine.


Efonidipine is primarily metabolized in the liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit activity as calcium antagonists. The vasodilating properties of DBZ and DPH were about two-thirds and one-third respectively than that of the parent compound. Results suggest that the majority of the pharmacological effect after oral dosing of Efonidipine hydrochloride in man is due to unchanged compound and its metabolites make a small contribution to the pharmacological effect.[14]


Biliary route is the main pathway of excretion. No significant amount of unchanged drug was excreted in urine. In the urine collected for 24 h after an oral dosing, 1.1 % of the dose was excreted as deaminated Efonidipine, and 0.5% as a pyridine analogue of deaminated Efonidipine.


  • Essential hypertension and renal parenchymal hypertension
  • Angina

Dosage and Administration

  • Essential hypertension and renal parenchymal hypertension: 20-40 mg orally once daily. A dose of up to 80mg/day is seen to be safe and effective in clinical trials.[15][16]
  • Angina: 40 mg/day.


  • Contraindicated in patients hypersensitive to Efonidipine or any of the excipients
  •  It is also contraindicated in pregnancy and lactation.


  •  Should be administered with caution in patients with hepatic impairment
  • Dose adjustment may be required in elderly as hypotension can occur
  •  Efonidipine may worsen clinical condition in patients with sinus bradycardia, sinus arrest or sinus node dysfunction
  • As dizziness can occur due to hypotensive action, one should be careful while operating machines, with aerial work platforms and driving of a motor vehicle
  • Drug should not be stopped abruptly. Discontinuation should be gradual and under supervision of a qualified physician

Drug Interactions

  • Other anti-hypertensive agents: Efonidipine enhances the antihypertensive action additively and may produce hypotension and shock. Blood pressure should be monitored regularly to adjust dose of concomitant drugs.
  •  Cimetidine: Cimetidine inhibits CYP450 enzymes involved in metabolism of CCBs. Blood concentration of calcium channel antagonists increase leading to higher incidence of side effects (hot flushes).
  • Grape fruit juice: Grapefruit juice suppresses enzymes metabolizing calcium channel antagonists (cytochrome P450) and reduces the clearance. Thus, there is a possibility that blood concentration of the drug may increase and the anti-hypertensive effect is enhanced.
  • Tacrolimus: Efonidipine inhibits metabolic enzymes involved in Tacrolimus metabolism and reduces its clearance. So, increase in blood concentration of Tacrolimus can occur.

Adverse Drug Reactions

The common side effects are hot flushes, facial flushing and headache. In addition, elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may occur. Frequent urination, pedal edema, increased triglycerides occurs in less than 0.1%.[17]

Lesser incidence of pedal edema (< 0.1%)

One common adverse effect of the L-type Ca2+ channel blockers like Amlodipine is vasodilatory Pedal edema. Combined L-/T-type Ca2+ channel blockers, such as Efonidipine, display antihypertensive efficacy similar to their predecessors (Amlodipine) with much less propensity of pedal edema formation. Efonidipine equalizes the hydrostatic pressure across the capillary bed through equal arteriolar and venular dilatation, thus reducing vasodilatory edema. These incremental microcirculatory benefits of efonidipine over the conventional L-type Ca2+ channel blockers (Amlodipine) are likely attributed to their additional T-type Ca2+ channel blocking properties and the increased presence of T-type Ca2+channels in the microvasculature (e.g. arterioles, capillaries, venules etc).[18]

Among the CCBs, Efonidipine (<0.1%)[17] has lowest incidence of pedal edema compared to amlodipine ( 5-16%)[19], cilnidipine (5%)[20], benidipine (5%)[21] and azelnidipine (15.5%).[22]

Use in Special Population

Administration to Elderly

The drug should be started at low dose (20 mg/day) in elderly. Patient should be carefully observed for development of hypo-tension. Dose may be halved if there is intolerance to the 20 mg/day dosage regimen.

Pregnancy and Lactation

The drug should not be administered to pregnant women and women suspected of being pregnant. Administration to lactating women should be avoided unless benefit significantly surpasses the risk to the child. Mothers on Efonidipine treatment should avoid breast feeding.

Pediatric Use

Safety of Efonidipine in low birth weight infants, newborns, infants and children has not been established.

Efonidipine-The Best in Class

Efonidipine is unique among clinically available CCBs. Its antihypertensive efficacy is superior or at par with other CCBs. But, in terms of pleiotropic effects leading to enhanced cerebral, cardiac and renal protection, Efonidipine scores over the other CCBs.

Advantages over Amlodipine

1.      Better renoprotection by:

  • Dual channel blockade [1]
  • Prevention of Rho-kinase and NFkB induced tubulointerstitial fibrosis[23][24]
  • Reduction of synthesis and secretion of aldosterone from the adrenal cortex[25]

2.       Preferred in  angina  with hypertension due to negative chronotropic action[26]

3.       Better control of reflex tachycardia[3]

4.       Reduces cardiac remodelling, arterial stiffness and prevents atherogenesis[27]

5.       More useful in patients with diabetes & nephropathy[28]

6.       Better protection  against cardiac hypertrophy by significant reduction in LVMI[29]

7.       Less adverse effects compared to Amlodipine[30]

8.       Reduces endothelial dysfunction and oxidative stress(anti-oxidant property)[10]

Advantages over Cilnidipine

1.       Strong negative chronotropic effect (less tachycardia) compared to Cilnidipine[3]

2.       Significant improvement in exercise tolerance.[31]Better choice in hypertensive patients with angina.

3.       Better BP control by marked urinary Na+ excretion[32]

4.       Better renoprotection by:

  • a.      Suppression of plasma renin release[33]
  • b.     Prevention of Rho-kinase and NFkB induced tubulointerstitial fibrosis[34][35]
  • c.      Reduction of synthesis and secretion of aldosterone from the adrenal cortex[5]

5.       Better choice in diabetic hypertensives[36]

6.       Prevents cardiac remodelling by suppression of aldosterone secretion[5]

7.       Superior anti-oxidant activity[10]

8.       Less adverse effects compared to Cilnidipine[30]

Advantages over Benidipine

L & T-type CCBs have invoked a lot of interest in the management of hypertension because of their unique pharmacological profile. Several novel agents have been developed including Azelnidipine, Barnidipine, Benidipine, Efonidipine, Manidipine and Nilvadipine. Among all the agents, Efonidipine has emerged as the best among its peers. The advantages of Efonidipine over Benidipine are summarized below.

1. More selective blockade of T-type calcium channels [37][38]

2. More balanced renal arteriolar dilatation than benidipine[37][38]

3. Superior anti-proteinuric effect [15]

4. Greater reduction of serum aldosterone [39]

5. Renoprotection by reducing plasma renin unlike Benidipine [39]

6. Greater negative chronotropic effect

7. Efonidipine has anti-platelet activity[12]

8. Efonidipine reduces Insulin Resistance [40]

9. Significantly lower incidence of pedal edema & constipation compared to Benidipine

A new synthesis of efonidipine has been described: The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III), which, by treatment with iodoacetone (IV) in refluxing ether, yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII), which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.ReferencesChem Pharm Bull 1992,40(9),2362

A new synthesis for (4S)-efonidipine has been described: The reaction of 5,5-dimethyl-2-(2-oxopropyl)-1,3,2-dioxaphosphorinan-2-one (I) with dimorpholino(3-nitrophenyl)methane (II) by means of trifluoroacetic acid in hot toluene gives 5,5-dimethyl-2-[1-acetyl-2-(3-nitrophenyl)vinyl]-1,3,2-dioxaphosphorina n-2-one (III), which is cyclized with 3-aminocrotonic acid 2(S)-methoxy-2-phenylethyl ester (IV) in refluxing toluene; the recrystallization of the resulting product affords 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4(S)-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2(S)-methoxy-2-phenylethyl ester (V). The protection of the NH group of (V) with chloromethyl methyl ether and NaH in THF yields the N-methoxymethyl derivative (VI), which is transesterified with 2-(N-benzyl-N-methylamino)ethanol (VII) and NaH in DMSO, giving the protected final product (VIII). Finally, this compound is deprotected with HCl in ethanol.

An enantioselective synthesis of efonidipine has been described: The enantioselective hydrolysis of 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-n itrophenyl)-1,4-dihydropyridine-3-carboxylic acid propionyloxymethyl ester (I) with lipase AH in 2,5-dimethyltetrahydrofuran saturated with water gives the corresponding free acid of the (S)-isomer (III), while the propionyloxymethyl ester of the (R)-isomer (II) remains undisturbed. After chromatographic separation, the (R)-ester (II) is hydrolyzed with NaOH in methanol to the (R)-acid (IV). Finally, both enantiomerically pure acids (III) and (IV) are separately esterified with 2-(N-benzyl-N-phenylamino)ethanol in the usual way



Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium antagonistic and antihypertensive activities: Novel calcium-antagonist 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol (NZ-105) and its crystal structure
Chem Pharm Bull 1992, 40(9): 2362


IN 201501586

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Efonidipine structure.svg
Clinical data
Trade names Landel (ランデル)
AHFS/ International Drug Names
Routes of
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
CAS Number
PubChem CID
Chemical and physical data
Formula C34H38N3O7P
Molar mass 631.65 g/mol
3D model (JSmol)
Title: Efonidipine
CAS Registry Number: 111011-63-3
CAS Name: 5-(5,5-Dimethyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-[phenyl(phenylmethyl)amino]ethyl ester, P-oxide
Additional Names: 2-(N-benzylanilino)ethyl(±)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-5-phosphononicotinate, cyclic 2,2-dimethyltrimethylene ester
Molecular Formula: C34H38N3O7P
Molecular Weight: 631.66
Percent Composition: C 64.65%, H 6.06%, N 6.65%, O 17.73%, P 4.90%
Literature References: Dihydropyridine calcium channel blocker. Prepn: K. Seto et al., WO 8704439idem et al., US 4885284(1987, 1989 both to Nissan); and crystal structure: R. Sakoda et al., Chem. Pharm. Bull. 40, 2362 (1992). Stereoselective synthesis of enantiomers and crystal structure of (S)-form: idem et al., ibid. 2377. Pharmacology: C. Shudo et al., J. Pharm. Pharmacol. 45,525 (1993). Mechanism of action study: T. Yamashita et al., Jpn. J. Pharmacol. 57, 337 (1991). Clinical study: T. Saito et al., Curr. Ther. Res. 52, 113 (1992).
Properties: Crystals from ethyl acetate, mp 169-170° (Sakoda); also reported as mp 155-156° (Seto).
Melting point: mp 169-170° (Sakoda); mp 155-156° (Seto)
Derivative Type: Hydrochloride
CAS Registry Number: 111011-53-1
Molecular Formula: C34H38N3O7P.HCl
Molecular Weight: 668.12
Percent Composition: C 61.12%, H 5.88%, N 6.29%, O 16.76%, P 4.64%, Cl 5.31%
Properties: LD50 in mice (mg/kg): >600 orally (Seto).
Toxicity data: LD50 in mice (mg/kg): >600 orally (Seto)
Derivative Type: Hydrochloride ethanol
CAS Registry Number: 111011-76-8
Manufacturers’ Codes: NZ-105
Trademarks: Landel (Zeria)
Molecular Formula: C34H38N3O7P.C2H5OH.HCl
Molecular Weight: 714.18
Percent Composition: C 60.54%, H 6.35%, N 5.88%, O 17.92%, P 4.34%, Cl 4.96%
Properties: Yellow crystals from aq ethanol, mp 151° (dec).
Melting point: mp 151° (dec)
Derivative Type: (S)- or (R)-Form
Properties: Pale yellow crystals from ethanol, mp 190-192°. [a]D25 + or -7.0° resp (c = 0.50 in chloroform).
Melting point: mp 190-192°
Optical Rotation: [a]D25 + or -7.0° resp (c = 0.50 in chloroform)


  • Formula:C34H38N3O7P
  • MW:631.67 g/mol
  • CAS-RN:128194-13-8


  • Formula:C34H38N3O7P
  • MW:631.67 g/mol
  • CAS-RN:128194-12-7
Therap-Cat: Antihypertensive.
Keywords: Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

///////////Efonidipine, エホニジピン, IND 2017, Landel , NZ 105, Efonidipine Hydrochloride Ethanolate


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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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