Atrasentan

• 173937-91-2 
• as HCl: 195733-43-8

A-147627, (+)-A-127722, ABT-627,173937-91-2,

(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid

• UNII-V6D7VK2215

Endothelin ET-A antagonist

Diabetic nephropathy; End stage renal disease; Renal disease

FDA APPROVED 4/02/2025, Vanrafia, To reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression

Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer,^[1] including non-small cell lung cancer.^[2] It is also being investigated as a therapy for diabetic kidney disease.

Atrasentan failed a phase 3 trial for prostate cancer in patients unresponsive to hormone therapy.^[3] A second trial confirmed this finding.^[4]

It is an endothelin receptor antagonist selective for subtype A (ET_A). While other drugs of this type (sitaxentan, ambrisentan) exploit the vasoconstrictive properties of endothelin and are mainly used for the treatment of pulmonary arterial hypertension, atrasentan blocks endothelin induced cell proliferation.

In April 2014, de Zeeuw et al. showed that 0.5 mg and 1.25 mg of atrasentan reduced urinary albumin by 35 and 38% respectively with modest side effects. Patients also had decreased home blood pressures (but no change in office readings) decrease total cholesterol and LDL. Patients in the 1.25 mg dose group had increased weight gain which was presumably due to increased edema and had to withdraw from the study more than the placebo or 0.5 mg dose group.^[5] Reductions in proteinuria have been associated with beneficial patient outcomes in diabetic kidney disease with other interventions but is not an accepted end-point by the FDA.

The recently initiated SONAR trial^[6] will determine if atrasentan reduces kidney failure in diabetic kidney disease.

Useful for treating nephropathy and chronic kidney disease associated with Type II diabetes. For a prior filing see WO2015006219 , claiming the stable solid composition in the form of a tablet comprising atrasentan and an anti-oxidant. AbbVie (following its spin-out from Abbott), is developing atrasentan (phase III; February 2015) for treating chronic kidney disease, including diabetic nephropathy.

PAPER

European Journal of Organic Chemistry

Enantioselective Synthesis of the Pyrrolidine Core of Endothelin Antagonist ABT-627 (Atrasentan) via 1,2-Oxazines

Year:2003
Volume:2003
Issue:18
page:3524-3533

PATENT

http://www.google.com/patents/US20080132710

EXAMPLE 1

A mixture of bromoacetyl bromide (72.3 mL) in toluene (500 mL) at 0° C. was treated with dibutylamine (280 mL) in toluene (220 mL) while keeping the solution temperature below 10° C., stirred at 0° C. for 15 minutes, treated with 2.5% aqueous phosphoric acid (500 mL) and warmed to 25° C. The organic layer was isolated, washed with water (500 mL) and concentrated to provide the product as a solution in toluene.

EXAMPLE 25-((E)-2-nitroethenyl)-1,3-benzodioxole

3,4-methylenedioxybenzaldehyde (15.55 Kg) was treated sequentially with ammonium acetate (13.4 Kg,), acetic acid (45.2 Kg) and nitromethane (18.4 Kg), warmed to 70° C., stirred for 30 minutes, warmed to 80° C., stirred for 10 hours, cooled to 10° C. and filtered. The filtrant was washed with acetic acid (2×8 Kg) and water (2×90 Kg) and dried under a nitrogen stream then in under vacuum at 50° C. for 2 days.

EXAMPLE 3ethyl 3-(4-methoxyphenyl)-3-oxopropanoate

A mixture of potassium tert-amylate (50.8 Kg) in toluene (15.2 Kg) at 5° C. was treated with 4-methoxyacetophenone (6.755 Kg) and diethyl carbonate (6.4 Kg) in toluene over 1 hour while keeping the solution temperature below 10° C., warmed to 60° C. for 8 hours, cooled to 20° C. and treated with acetic acid (8 Kg) and water (90 Kg) over 30 minutes while keeping the solution temperature below 20° C. The organic layer was isolated, washed with 5% aqueous sodium bicarbonate (41 Kg) and concentrated at 50° C. to 14.65 Kg.

EXAMPLE 4ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1,3-benzodioxol-5-yl)butyrate

A mixture of EXAMPLE 3 (7.5 Kg) in THF (56 Kg) was treated with EXAMPLE 3 (8.4 Kg), cooled to 17° C., treated with sodium ethoxide (6.4 g), stirred for 30 minutes, treated with more sodium ethoxide (6.4 g), stirred at 25° C. until HPLC shows less than 1 area % ketoester remaining and concentrated to 32.2 Kg.

EXAMPLE 5ethyl cis,cis-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate

Raney nickel (20 g), from which the water had been decanted, was treated sequentially with THF (20 mL), EXAMPLE 4 (40.82 g), and acetic acid (2.75 mL). The mixture was stirred under hydrogen (60 psi) until hydrogen uptake slowed, treated with trifluoroacetic acid, stirred under hydrogen (200 psi) until HPLC shows no residual imine and less than 2% nitrone and filtered with a methanol (100 mL) wash. The filtrate, which contained 13.3 g of EXAMPLE 5, was concentrated with THF (200 mL) addition to 100 mL, neutralized with 2N aqueous NaOH (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2×100 mL). The extract was used in the next step.

EXAMPLE 6ethyl trans,trans-2-(4-methoxyphenyl)-4-(1,3 -benzodioxol-5 -yl)pyrrolidine-3-carboxylate

Example 501E (38.1 g) was concentrated with ethanol (200 mL) addition to 100 mL, treated with sodium ethoxide (3.4 g), heated to 75° C., cooled to 25° C. when HPLC showed less than 3% of EXAMPLE 1E and concentrated. The concentrate was mixed with isopropyl acetate (400 mL), washed with water (2×150 mL) and extracted with 0.25 M phosphoric acid (2×400 mL). The extract was mixed with ethyl acetate (200 mL) and neutralized to pH 7 with sodium bicarbonate (21 g), and the organic layer was isolated.

EXAMPLE 7ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate

EXAMPLE 501F was concentrated with acetonitrile (100 mL) addition to 50 mL, treated with (S)-(+)-mandelic acid (2.06 g), stirred until a solution formed, stirred for 16 hours, cooled to 0° C., stirred for 5 hours and filtered. The filtrant was dried at 50° C. under a nitrogen stream for 1 day. The purity of the product was determined by chiral HPLC using Chiralpak AS with 95:5:0.05 hexane/ethanol/diethylamine, a flow rate of 1 mL/min. and UV detection at 227 nm. Retention times were 15.5 minutes for the (+)-enantiomer and 21.0 minutes for the (−)-enantiomer.

EXAMPLE 8(2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid

A mixture of EXAMPLE 7 (20 g) in ethyl acetate (150 mL) and 5% aqueous sodium bicarbonate was stirred at 25° C. until the salt dissolved and gas evolution stopped. The organic layer was isolated and concentrated. The concentrate was treated with acetonitrile (200 mL), concentrated to 100 mL, cooled to 10° C., treated with diisopropylethylamine (11.8 mL) and EXAMPLE 1 (10.5 g), stirred for 12 hours and concentrated. The concentrate was treated with ethanol (200 mL), concentrated to 100 mL, treated with 40% aqueous NaOH (20 mL), stirred at 60° C. for 4 hours, cooled, poured into water (400 mL), washed with hexanes (2×50 mL then 2×20 mL), treated with ethyl acetate (400 mL) and adjusted to pH 5 with concentrated HCl (12 mL). The organic layer was isolated and concentrated.

………………….

The Michael reaction between 3,4-(methylenedioxy)-beta-nitrostyrene (I) and ethyl (4-methoxybenzoyl)acetate (II) in the presence of DBU gave adduct (III) as a mixture of isomers. Hydrogenation of this nitro ketone over Raney-Ni afforded, after spontaneous cyclization of the resulting amino ketone, the pyrroline (IV). Further reduction of the imine with NaBH3CN yielded a mixture of three pyrrolidine isomers. The desired trans-trans isomer (VI) could not be separated from the cis-trans isomer by column chromatography. However, the pure cis-cis compound (V) was isomerized to (VI) with NaOEt in refluxing EtOH. The protection of the amine as the tert-butyl carbamate with Boc2O, and saponification of the ester function provided the racemic acid (VII). Resolution of (VII) was achieved by conversion to the mixed anhydride (VIII) with pivaloyl chloride, followed by condensation with the lithium salt of (S)-4-benzyl-2-oxazolidinone (IX), and chromatographic separation of the resulting diastereomeric imides. Alternatively, racemic (VII) could be resolved by crystallization of its salt with (R)-a-methylbenzylamine. Removal of the Boc group from the appropriate isomer (X) with HCl in dioxan, followed by alkylation with N,N-dibutylbromoacetamide (XI) in the presence of i-Pr2NEt furnished the pyrrolidinylacetamide (XII). Finally, hydrolysis of the imide with lithium hydroperoxide provided the target acid.

Cyclization of 5-(2-nitrovinyl)-1,3-benzodioxole (I) with ethyl 2-(4-methoxybenzoyl)acetate (II) by means of DBU in THF gives the 4-nitrobutyrate (III), which is reduced with H2 over Ni in ethanol to the corresponding amine, which undergoes immediate cyclization to give the pyrroline carboxylate (IV). Reduction of pyrroline (IV) with NaCNBH3 in THF affords the expected pyrrolidine as a mixture of the (trans,trans)-(V), (cis,cis)-(VI) and (cis,trans)-(VII) isomers. Using chromatography on silica gel, only the (cis,cis)-isomer (VI) is separated and completely isomerized to the (trans,trans)-isomer (V) by treatment with NaOEt in refluxing ethanol. Pure (trans,trans)-isomer (V) or the remaining mixture of (trans,trans)-(V) and (cis,trans)-(VII) is N-protected with Boc2O in dichloromethane to provide a mixture of carbamates. Then hydrolysis of the esters is performed with NaOH in ethanol/water at room temperature, and under these conditions only the (trans,trans)-isomer hydrolyzes, giving the racemic (trans,trans)-acid (VIII). Unreacted (cis,trans)-ester (VII) is easily removed by conventional methods. Condensation of the racemic acid (VIII) with the lithium salt of the chiral oxazolidinone (IX) by means of pivaloyl chloride yields the corresponding amide as a diastereomeric mixture of (X) and (XI) that are separated by chromatography. The desired isomer (XI) is deprotected with HCl in dioxane to afford the chiral pyrrolidine (XII), which is condensed with 2-bromo-N,N-dibutylacetamide (XIII) by means of diisopropylamine in acetonitrile to give the adduct (XIV). Finally, the chiral auxiliary of (XIV) is eliminated by means of LiOOH (LiOH + H2O2) in water.

SYN

Condensation of ketoester (I) with nitrovinyl benzodioxole (II) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene gave adduct (III). Hydrogenation of the nitro group of (III) over Raney Nickel with concomitant cyclization yielded dihydropyrrole (IV). Further reduction of (IV) with sodium cyanoborohydride provided a mixture of diastereomeric pyrrolidines. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans products (V). N-Alkylation of the pyrrolidine (V) with N,N-dibutyl bromoacetamide (VI) furnished (VIIa-b). Finally, selective hydrolysis of the ester group from the trans,trans isomer produced a mixture of cis,trans ester (VIII) and the target trans,trans acid, which were readily separated by fractional extraction.

SYN

SYN

J Med Chem 1996,39(5),1039

The Michael reaction between 3,4-(methylenedioxy)-beta-nitrostyrene (I) and ethyl (4-methoxybenzoyl)acetate (II) in the presence of DBU gave adduct (III) as a mixture of isomers. Hydrogenation of this nitro ketone over Raney-Ni afforded, after spontaneous cyclization of the resulting amino ketone, the pyrroline (IV). Further reduction of the imine with NaBH3CN yielded a mixture of three pyrrolidine isomers. The desired trans-trans isomer (VI) could not be separated from the cis-trans isomer by column chromatography. However, the pure cis-cis compound (V) was isomerized to (VI) with NaOEt in refluxing EtOH. The protection of the amine as the tert-butyl carbamate with Boc2O, and saponification of the ester function provided the racemic acid (VII). Resolution of (VII) was achieved by conversion to the mixed anhydride (VIII) with pivaloyl chloride, followed by condensation with the lithium salt of (S)-4-benzyl-2-oxazolidinone (IX), and chromatographic separation of the resulting diastereomeric imides. Alternatively, racemic (VII) could be resolved by crystallization of its salt with (R)-a-methylbenzylamine. Removal of the Boc group from the appropriate isomer (X) with HCl in dioxan, followed by alkylation with N,N-dibutylbromoacetamide (XI) in the presence of i-Pr2NEt furnished the pyrrolidinylacetamide (XII). Finally, hydrolysis of the imide with lithium hydroperoxide provided the target acid.

SYN

Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3璗HF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.

References

1

• “Atrasentan”. NCI Dictionary of Cancer Terms. National Institute of Cancer.
• 2
• Chiappori, Alberto A.; Haura, Eric; Rodriguez, Francisco A.; Boulware, David; Kapoor, Rachna; Neuger, Anthony M.; Lush, Richard; Padilla, Barbara; Burton, Michelle; Williams, Charles; Simon, George; Antonia, Scott; Sullivan, Daniel M.; Bepler, Gerold (March 2008). “Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer”. Clinical Cancer Research 14 (5): 1464–9. doi:10.1158/1078-0432.CCR-07-1508. PMID 18316570.
• 3
• “Addition of experimental drug to standard chemotherapy for advanced prostate cancer shows no benefit in phase 3 clinical trial” (Press release). National Cancer Institute. April 21, 2011. Retrieved October 18, 2014.
• 4
• Quinn, David I; Tangen, Catherine M; Hussain, Maha; Lara, Primo N; Goldkorn, Amir; Moinpour, Carol M; Garzotto, Mark G; Mack, Philip C; Carducci, Michael A; Monk, J Paul; Twardowski, Przemyslaw W; Van Veldhuizen, Peter J; Agarwal, Neeraj; Higano, Celestia S; Vogelzang, Nicholas J; Thompson, Ian M (August 2013). “Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial”. The Lancet Oncology 14 (9): 893–900. doi:10.1016/S1470-2045(13)70294-8. PMID 23871417.
• 5
• de Zeeuw, Dick; Coll, Blai; Andress, Dennis; Brennan, John J.; Tang, Hui; Houser, Mark; Correa-Rotter, Ricardo; Kohan, Donald; Lambers Heerspink, Hiddo J.; Makino, Hirofumi; Perkovic, Vlado; Pritchett, Yili; Remuzzi, Giuseppe; Tobe, Sheldon W.; Toto, Robert; Viberti, Giancarlo; Parving, Hans-Henrik (May 2014). “The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy”. Journal of the American Society of Nephrology 25 (5): 1083–93. doi:10.1681/ASN.2013080830. PMID 24722445.
• 6

Clinical trial number NCT01858532 for “Study Of Diabetic Nephropathy With Atrasentan (SONAR)” at ClinicalTrials.gov

US-8962675, AbbVie Inc

Granted in February 2015, this patent claims novel crystalline anhydrous S-mandelate salt of atrasentan. Useful for treating nephropathy and chronic kidney disease associated with Type II diabetes.

Atrasentan

Systematic (IUPAC) name
(2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid
Clinical data
Legal status	?
Identifiers
CAS number	173937-91-2
ATC code	None
PubChem	CID 159594
ChemSpider	140321
UNII	V6D7VK2215
ChEMBL	CHEMBL9194
Chemical data
Formula	C29H38N2O6
Molecular mass	510.621 g/mol

READ MORE  ON SENTAN SERIES………..http://medcheminternational.blogspot.in/p/sentan-series.html

1. Szczepankiewicz BG, Bal RB, von Geldern TW, Wu-Wong JR, Chiou WJ, Dixon DB, Opgenorth TJ, Hoffman DJ, Borre AJ, Marsh KC, Nguyen BN: The effects of diminishing albumin binding to some Endothelin receptor antagonists. Life Sci. 1998;63(21):1905-12. doi: 10.1016/s0024-3205(98)00466-4. [Article]
2. Rajasekaran A, Julian BA, Rizk DV: IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci. 2021 Feb;361(2):176-194. doi: 10.1016/j.amjms.2020.10.003. Epub 2020 Oct 8. [Article]
3. FDA Approved Drug Products: Vanrafia (atrasentan) tablets for oral use (April 2025) [Link]
4. Novartis Media Release: Novartis receives FDA accelerated approval for Vanrafia® (atrasentan), the first and only selective endothelin A receptor antagonist for proteinuria reduction in primary IgA nephropathy (IgAN) [Link]
5. StatPearls [Internet]: IgA Nephropathy (Berger Disease) [Link]
6. ResearchGate: Total Synthesis of Atrasentan (Craig S. Harris, Reims Symposium, October 2002) [Link]

//////////ATRASENTAN, FDA 2025, APPROVALS 2025, Vanrafia, A 147627, (+)-A-127722, ABT 627, UNII-V6D7VK2215