- Molecular FormulaC23H28N8
- Average mass416.522 Da
PHASE 2, PFIZER, HYPERTENSION
Forasartan, a specific angiotensin II antagonist, is used alone or with other antihypertensive agents to treat hypertension. Forasartan competes with angiotensin II for binding at the AT1 receptor subtype. As angiotensin II is a vasoconstrictor which also stimulates the synthesis and release of aldosterone, blockage of its effects results in a decreases in systemic vascular resistance.
Forasartan is indicated for the treatment of hypertension and, similar to other ARBs, it protects the kidneys from kidney blood vessel damage caused by increased kidney blood pressure by blocking renin–angiotensin system activation.
Forasartan is administered in the active oral form  which means that it must go through first pass metabolism in the liver. The dose administered ranges between 150 mg-200 mg daily. Increasing to more than 200 mg daily does not offer significantly greater AT1 receptor inhibition. Forasartan is absorbed quickly in the GI, and within an hour it becomes significantly biologically active. Peak plasma concentrations of the drug are reached within one hour.
2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yI)methyl]- 2-pyridinyl]benzoic acid
Step 1 : Preparation of 2-bromo-5-picoline .
A solution of 1500 mL (14 mol) of 48%
hydrobromic acid was cooled to 10 °C and 300 g (2.8 mol) of 2-amino-5-picoline (Aldrich) was added slowly. The
solution was maintained at or below 0 °C while 450 mL (8.8 mol) of bromime was added dropwise. After the bromine addition was complete, a solution of 500 g (7.3 mol) of sodium nitrite in 1000 mL of water was added slowly over 6 h. The reaction pH was adjusted by the careful addition of 1500 mL (56 mol) of 50% sodium hydroxide at such a rate that the temperature was maintained below 30 °C. The product precipitated from the nearly colorless reaction mixture; filtration gave 450 g (94%) of 2-bromo-5-picoline as a yellow powder: mp 38-40 °C; NMR 7.27 (s, 1H), 7.28 (s, 1H), 7.12 (br s, 1H).
Step 2 : Preparation of N-methyl-N-tertbutylbenzamide.
Under nitrogen, 96.7 g (1.1 mol) of N-methyl-N-tertbutylamine and 111 g (1.1 mol) of triethylamine was dissolved in 1050 mL of anhydrous tetrahydrofuran (THF).
The solution was cooled to 0 °C and treated with 140.6 σ (1.0 mol) of benzoyl chloride. The reaction was allowed to slowly warm to ambient temperature and stir overnight.
Filtration and subsequent concentration in vacuo of the filtrate gave the crude product which was purified by sublimation (65 °, 0.2 torr) to give 184 g (96%) of
colorless N-methyl-N-tertbutybenzamide: mp 80.5-82.0 °C; NMR (CDCI3) δ1.52 (s, 9H), 2.87 (s, 3H), 7.34-7.40 (m, 3H), 7.40-7.46 (m, 2H).
Step 3 : Preparation of 2-(N-methyl-N-tertbutylcarboxamido)phenyIboronic acid.
Under nitrogen, a solution of 50.0 g (262 mmol) of N-methyl-N-tertbutylbenzamide from step 2 and 44 ml (2S2 mmol) of tetramethylethylenediamine (TMEDA) in 3350 mL of anhydrous THF was cooled to -78 °C and slowly treated with 262 mmol of sec-butyllithium in cyclohexane. After 1 h at -78 °C, the reaction was treated with 45 mL (393 mmol) of trimethyl borate and allowed to slowly warm to ambient temperature overnight with stirring. The reaction was concentrated in vacuo; the residue was dissolved in IK sodium hydroxide and extracted with methylene chloride. The pH of the aqueous phase was adjusted to six with dilute hydrochloric acid and extracted with methylene chloride; the organic layer was dried (MgSO4) and concentrated in vacuo to give 55.7 g (90%) of a 80:20 mixture of syn/anti isomers of 2-(N-methyl-N-tertbutylcarboxamido)phenyIboronic acid as a pale yellow glass: NMR (CDCI3) δ 1.30 (s, syn C(CH3)3, 7.3H), 1.54 (s, anti 0(0.3)3, 1.7H), 2.81 (s, anti CH3, 0.6H), 2.94 (s, syn CH3, 2.4H), 7.29-7.46 (m, 3H), 7.95-8.01 (m, 1H).
step 4 : Preparation of N-methyl-N-tertbwtyl-2-(5-methyl-2-pyridinyl)benzamide.
Under nitrogen, 4.44 g (25.8 mmcl) cf 2-bromo-5-picoline from step 1 in 60 mL of toluene was treated with 6.75 g (29 mmol) of 2- (N-methyl-N- tertbutylcarboxamido)phenyIboronic acid from step 3, 1.0 g of tetrakis (triphenylphosphine)palladium zero, 26 mL of ethanol, and 29 mL of 2M sodium carbonate; this mixture was heated to reflux and vigorously stirred for 24 h. The reaction was partitioned between water and ether; the organic layer was separated, dried (MgSθ4), and
concentrated in vacuo. Purification by silica gel
chromatography (Waters Prep-500A) using ethyl
acetate/hexane (1:2) gave 6.51 g (90%) of N-methyl-N- tertbutyl-2-(5-methyl-2-pyridinyl)benzamide as an oil : NMR (CDCI3) δ 1.40 (s, 9H), 2.33 (s, 3H), 2.61 (s, 3H), 7.27- 7.33 (m, 1H), 7.35-7.41 (m, 2H), 7.47-7.51 (m, 2H), 7.60- 7.66 (m, 1H), 8.43 (br s, 1H).
Step 5 : Preparation of sodium 2-(5-methyl-2- pyridinyl)benzoate.
Under nitrogen, 6.5 g (23 mmol) of N-methyl-N- tertbutyl-2-(6-methyl-3-pyridinyl)benzamide from step 4 was treated with 65 mL of anhydrous trifluoroacetic acid (TFA) at reflux for 6 h. The reaction was concentrated in vacuo and the residue dissolved in water. The pH was adjusted to 10 with aqueous sodium hydroxide and lyophilized to give the sodium salt of 2- (5-methyl-2-pyridinyl)benzoic acid as a colorless solid: NMR [CDCI3/CF3CO2H (97:3)] δ 2.62 (s, 3H), 7.42-7.48 (m, 1H), 7.67-7.80 (m, 3H), 8.18-8.24 (m, 1H), 8.28 (dd, J=8 and 2 HZ, 1H), 7.67-7.80 (m, 3H), 8.18-8.24 (m, 1H), 8.28 (dd, J=8 and 2 Hz, 1H), 8.61 (s, 1H) ; MS (FAB) m/e (rel intensity) 214 (20), 196 (100); HRMS.
Calc’d for M+H: 214.0868. Found: 214.0846.
step 6 : Preparation of ethyl 2-(5-methyl-2-pyridinyl)benzoate.
Under nitrogen, the crude sodium salt from step 5 was suspended in 50 mL of chloroform and treated with 9 mL (103 mmol) of oxalyl chloride. The reaction was stirred for 72 h, filtered under nitrogen, and concentrated in vacuo; the residue was dissolved in absolute ethanol.
Concentration in vacuo gave 2.0 g (8 mmol) of ethyl 2-(5-methyl-2-pyridinyl)benzoate as a brown oil: NMR (CDCI3) δ 1.09 (t, J=7 Hz, 3H), 2.36 (s, 3H), 4.15 (q, J=7 Hz, 2H), 7.34 (d, J=8 Hz, 1H), 7.38-7.48 (m, 1H), 7.48-7.58 (m, 3H), 7.80 (d, J=8 Hz, 1H), 8.46 (s, 1H).
Step 7 : Preparation of ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate.
Under nitrogen, the crude ethyl 2-(5-methyl-2-pyridinyl)benzoate from step 6 was treated with 1.7 g (9.5 mmol) of NBS and 160 mg (0.66 mmol) of benzoyl peroxide in 145 mL of anhydrous carbon tetrachloride at reflux for 2.5 h. The reaction was filtered under nitrogen and
concentrated in vacuo to give crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate; no purification was attempted.
step 8 : Preparation of ethyl 2-[5-[(3,5-dibutyl-1H- 1 , 2 , 4-triazol-1 -yl )methy] 1 -2-pyridinyl ] benzoate .
Under nitrogen, 630 mg (3.5 mmol) of 3,5-dibutyl-1H-1,2,4-triazole from step 3 of Example 1 was added in small portions to 5.4 mmol of sodium hydride in 8 mL of DMF; stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 0 °C and treated with a solution of the crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate from step 7 in 10 mL of DMF. The reaction was stirred at ambient temperature overnight, quench with 1 mL of absolute ethanol, and concentrated in vacuo; the resulting residue was redisolved in methylene chloride, filtered, and reconcentrated in vacuo to give crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate.
step 9 : Preparation of 2- [5- [ (3, 5-dibutyl-1H-1 , 2, 4 -triazol-1-yl)methyl]-2-pyridinyllbenzoic acid.
A 1.0 g sample of the crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate from step 8 in 10 mL of water was treated with 3 mL of 101 aqueous sodium hydroxide and stirred at ambient temperature overnight. The reaction mixture was washed with 30 mL of ether and the pH adjusted to six with dilute hydrochloric acid. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic acetonitrile/water (28:72) (0.05% TFA) gave 5 mg of 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoic acid: NMR (D2O + NaO3S(CH2)3 Si(CH3)3] δ 0.80 (t, J=7 Hz, 3H), 0.86 (t, J=7 Hz, 3H), 1.19-1.33 (m, 4H), 1.54-1.68 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.82 (t, _ϊ=7 Hz, 2H), 5.43 (s, 2H), 7.45-7.59 (m, 5H), 7.64 (dd, J=8 and 2 Hz, 1H), 8.37-8.45 (m, 1H); MS (FAB) m/e (rel intensity) 393 (80), 375 (30), 212 (40), 182 (100); HRMS. Calc’d for M+Li: 399.2373. Found:
Step 1 : Preparation of 2-bromo-5-bromomethylpyridine.
A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 1 of Example 2 in 6000 mL of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g (173 mmol) of
azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCI3 δ 4.42 (s, 2H), 7.48 (d, .J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H).
Step 2: Preparation of 2-bromo-5-[(3.5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine.
Under nitrogen, 3.15 g (17 mmol) of solid 3,5-dibutyl-1H-1,2,4-triazole from step 3 of Example 1 was added in small portions to 33 mmol of sodium hydride in 31 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 0 °C and treated with a solution of 7.9 g (19 mmol) of crude 2-bromo-5-bromomethylpyridine from step 1 in 10 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the
DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4).
Silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (60:40) gave 4.8 g (47%) of 2-bromo-5-[(3,5- dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine as an oil: NMR (CDCI3) δ 0.88 (t, J=7 Hz, 1H), 0.92 (t, J=7 Hz, 1H), 1.27-1.44 (m, 4H), 1.59-1.76 (m, 4H), 2.60-2.71 (m, 4H), 5.18 (s, 2H), 7.35 (dd, J=8 and 3 Hz), 7.46 (d, J=8 Hz, 1H), 8.23 (d, .1=3 Hz, 1H).
Step 3: Preparation of 5-[2-[5-[(3,5-dibutyl-1H-1,2,4- triazol-1-yl)methyl]-2-pyridinyl]phenyl]-1H-tetrazole.
Under nitrogen, 1.03 g (2.9 mmol) of 2-bromo-5- [(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine from step 2 and 2.46 g (5.7 mmol) of 2-(N-triphenyImethyltetrazol-5-yl)phenyIboronic acid from step 5 of Example 1 were treated with 1.0 g (0.86 mmol) of tetrakis (triphenyl-phosphine)palladium zero, 15 mL of toluene, 10 mL of ethanol, and 6.3 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product was purified by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (20-40:80-60) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the
acetonitrile removed in vacuo, the pH adjusted to four with dilute sodium hydroxide, and the resulting suspension extracted 4 times with ether. The extracts were combined, dried (MgSθ4), and concentrated in vacuo to give 340 mg (28%) of 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole as a colorless solid: mp 139-141 °C; NMR (CD3OD) δ 0.90 (t, J=7 Hz, 3H), 0.93 (t, J=7 Hz, 3H), 1.29-1.44 (m, 4H), 1.58-1.75 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.81 (t, J=7 Hz, 2H), 5.40 (s, 2H), 7.47 (d, J=8 Hz, 1H), 7.61-7.77 (m, 5H), 8.33 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 417 (100), 208 (30); HRMS. Calc’d for M+H: 417.2515. Found: 417.2527.
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The angiotensin II receptor, type 1
Angiotensin II binds to AT1 receptors, increases contraction of vascular smooth muscle, and stimulates aldosterone resulting in sodium reabsorption and increase in blood volume. Smooth muscle contraction occurs due to increased calcium influx through the L-type calcium channels in smooth muscle cells during the plateau component, increasing the intracellular calcium and membrane potential which sustain depolarization and contraction.
Forasartan is a competitive and reversible ARB that competes with the angiotensin II binding site on AT1 and relaxes vascular smooth muscle, resulting in decreased blood pressure. Forasartan has a high affinity for the AT1 receptor (IC50=2.9 +/- 0.1nM). In dogs, it was found to block the pressor response of Angiotensin II with maximal inhibition, 91%. Forasartan administration selectively inhibits L-type calcium channels in the plateau component of the smooth muscle cells, favoring relaxation of the smooth muscle. Forasartan also decreases heart rate by inhibiting the positive chronotropic effect of high frequency preganglionic stimuli.
Even though experiments have been conducted on rabbits, guinea pigs, dogs  and humans, forasartan is not a popular drug of choice for hypertension due to its short duration of action; forasartan is less effective than losartan. Research demonstrates that forasartan is also significantly less potent than losartan.
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|Elimination half-life||1–2 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||416.533 g·mol−1|
|3D model (JSmol)|
////////SC-52458, FORASARTAN, форасартан , فوراسارتان , 福拉沙坦 , PHASE 2, PFIZER, HYPERTENSION