Atrasentan

Atrasentan
Clinical data
ATC code	none;
Identifiers
	IUPAC name (2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid;
CAS Number	173937-91-2 ;
PubChem CID	159594;
ChemSpider	140321 ;
UNII	V6D7VK2215;
ChEMBL	ChEMBL9194 ;
ECHA InfoCard	100.206.784
Chemical and physical data
Formula	C29H38N2O6
Molar mass	510.631 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(O)[C@H]4[C@H](c1ccc(OC)cc1)N(CC(=O)N(CCCC)CCCC)C[C@@H]4c2ccc3OCOc3c2;
	InChI InChI=1S/C29H38N2O6/c1-4-6-14-30(15-7-5-2)26(32)18-31-17-23(21-10-13-24-25(16-21)37-19-36-24)27(29(33)34)28(31)20-8-11-22(35-3)12-9-20/h8-13,16,23,27-28H,4-7,14-15,17-19H2,1-3H3,(H,33,34)/t23-,27-,28+/m1/s1 ; Key:MOTJMGVDPWRKOC-QPVYNBJUSA-N ;
	(what is this?) (verify)

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 0.75 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 0.75 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.

In 2013, SONAR trial[6] was initiated to determine if atrasentan reduces kidney failure in diabetic kidney disease.[7]

References

"Atrasentan". NCI Dictionary of Cancer Terms. National Institute of Cancer. 2011-02-02.
Chiappori AA, Haura E, Rodriguez FA, Boulware D, Kapoor R, Neuger AM, et al. (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.
"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.
Quinn DI, Tangen CM, Hussain M, Lara PN, Goldkorn A, Moinpour CM, et al. (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. PMC 4277263. PMID 23871417.
de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, et al. (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. PMC 4005314. PMID 24722445.
Clinical trial number NCT01858532 for "Study Of Diabetic Nephropathy With Atrasentan (SONAR)" at ClinicalTrials.gov
Heerspink HJ, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, et al. (May 2019). "Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial". Lancet. 393 (10184): 1937–1947. doi:10.1016/S0140-6736(19)30772-X. PMID 30995972. S2CID 113407761.

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[1] "Atrasentan". NCI Dictionary of Cancer Terms. National Institute of Cancer. 2011-02-02.

[2] Chiappori AA, Haura E, Rodriguez FA, Boulware D, Kapoor R, Neuger AM, et al. (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 DI, Tangen CM, Hussain M, Lara PN, Goldkorn A, Moinpour CM, et al. (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. PMC 4277263. PMID 23871417.

[5] Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, et al. (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. PMC 4005314. PMID 24722445.

[6] Clinical trial number NCT01858532 for "Study Of Diabetic Nephropathy With Atrasentan (SONAR)" at ClinicalTrials.gov

[HeerspinkParving2019-7] Heerspink HJ, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, et al. (May 2019). "Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial". Lancet. 393 (10184): 1937–1947. doi:10.1016/S0140-6736(19)30772-X. PMID 30995972. S2CID 113407761.