Danicopan free base | CAS#1903768-17-1 | FD inhibitor

MedKoo Cat#: 207093 | Name: Danicopan free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Danicopan, aslo known as ACH-4471 and ACH-0144471, is a highly potent, orally active Factor D inhibitor. Danicopan selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

Chemical Structure

Danicopan free base

CAS#1903768-17-1 (free base)

Theoretical Analysis

MedKoo Cat#: 207093

Name: Danicopan free base

CAS#: 1903768-17-1 (free base)

Chemical Formula: C26H23BrFN7O3

Exact Mass: 579.1030

Molecular Weight: 580.42

Elemental Analysis: C, 53.80; H, 3.99; Br, 13.77; F, 3.27; N, 16.89; O, 8.27

Price and Availability

Size	Price	Availability
100mg	USD 1,450.00	2 Weeks
200mg	USD 2,250.00	2 Weeks
500mg	USD 3,650.00	2 Weeks
1g	USD 4,650.00	2 Weeks
2g	USD 7,650.00	2 Weeks

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Related CAS #

1903768-17-1 (free base) Danicopan HCl

Synonym

Danicopan; ACH-4471; ACH4471; ACH 4471; ACH-0144471; ACH 0144471; ACH0144471; Danicopan free base

IUPAC/Chemical Name

(2S,4R)-1-{[3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol1-yl]acetyl}-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine2-carboxamide

InChi Key

PIBARDGJJAGJAJ-NQIIRXRSSA-N

InChi Code

InChI=1S/C26H23BrFN7O3/c1-14(36)25-19-8-16(17-10-29-15(2)30-11-17)6-7-20(19)35(33-25)13-24(37)34-12-18(28)9-21(34)26(38)32-23-5-3-4-22(27)31-23/h3-8,10-11,18,21H,9,12-13H2,1-2H3,(H,31,32,38)/t18-,21+/m1/s1

SMILES Code

O=C([C@H]1N(C(CN2N=C(C(C)=O)C3=C2C=CC(C4=CN=C(C)N=C4)=C3)=O)C[C@H](F)C1)NC5=NC(Br)=CC=C5

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Danicopan (ACH-4471), a small-molecule factor D inhibitor, shows high binding affinity to human Factor D (Kd value of 0.54 nM), inhibits alternative pathway of complement (APC) activity, and has potential to block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria (PNH) as well as atypical hemolytic uremic syndrome (aHUS).

In vitro activity:

ACH-3856 and ACH-4471 were evaluated in the modified Ham test by incubating PIGA-null cells with aHUS patient sera containing the Factor D inhibitors (Figure 4). PIGA-null cell killing activity in aHUS patient sera was heat-sensitive and therefore complement dependent. ACH-3856 (Figure 4A) and ACH-4471 (Figure 4B) both blocked the APC-mediated killing by aHUS patient sera at submicromolar concentrations. These results suggest that small-molecule Factor D inhibitors have the potential to mitigate complementmediated damage in aHUS patients, and support the utility of the modified Ham assay for preclinical aHUS drug assessment. Reference: Haematologica. 2017 Mar; 102(3): 466–475. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394948/

In vivo activity:

To profile the effects of continuous Factor D inhibition over a period of at least 24 hours in vivo, ACH-4471 was administered orally to 3 monkeys in two serial 200 mg/kg doses separated by 12 hours. The monkeys tolerated the compound well and showed no clinical abnormalities. Figure 5A shows ACH-4471 concentrations in plasma at time points from 0 hours (pre-dosing) to 30 hours (18 hours after the second dose). In parallel, serum was collected for determination of APC activity by Wieslab assay and of Factor D concentrations. APC activity was suppressed continuously by more than 95% continuously through the 30-hour time period (Figure 5B) with no significant increase in Factor D concentrations (Figure 5C). The observed stability of serum Factor D concentrations was expected because, as a small molecule, ACH-4471 should not interfere with renal Factor D clearance, in marked contrast to the effect of systemic delivery of the humanized monoclonal anti-Factor D antibody lampalizumab. These results demonstrate the potential utility of oral delivery of ACH-4471 for therapeutic inhibition of APC activation. Reference: Haematologica. 2017 Mar; 102(3): 466–475. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394948/

	Solvent	mg/mL	mM
Solubility
	DMSO	175.0	301.51

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 580.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Yuan X, Gavriilaki E, Thanassi JA, Yang G, Baines AC, Podos SD, Huang Y, Huang M, Brodsky RA. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica. 2017 Mar;102(3):466-475. doi: 10.3324/haematol.2016.153312. Epub 2016 Nov 3. PMID: 27810992; PMCID: PMC5394948.

In vitro protocol:

In vivo protocol:

1: Risitano AM, Kulasekararaj AG, Lee JW, Maciejewski JP, Notaro R, Brodsky R, Huang M, Geffner M, Browett P. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021 Dec 1;106(12):3188-3197. doi: 10.3324/haematol.2020.261826. PMID: 33121236; PMCID: PMC8634185. 2: Kulasekararaj AG, Risitano AM, Maciejewski JP, Notaro R, Browett P, Lee JW, Huang M, Geffner M, Brodsky RA. Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab. Blood. 2021 Nov 18;138(20):1928-1938. doi: 10.1182/blood.2021011388. PMID: 34314483; PMCID: PMC8602931. 3: Nester C, Appel GB, Bomback AS, Bouman KP, Cook HT, Daina E, Dixon BP, Rice K, Najafian N, Hui J, Podos SD, Langman CB, Lightstone L, Parikh SV, Pickering MC, Sperati CJ, Trachtman H, Tumlin J, de Vries AP, Wetzels JFM, Remuzzi G. Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies. Am J Nephrol. 2022;53(10):687-700. doi: 10.1159/000527167. Epub 2022 Nov 24. Erratum in: Am J Nephrol. 2023 Jan 19;:1. PMID: 36423588. 4: Boyer DD, Ko YP, Podos SD, Cartwright ME, Gao X, Wiles JA, Huang M. Danicopan, an Oral Complement Factor D Inhibitor, Exhibits High and Sustained Exposure in Ocular Tissues in Preclinical Studies. Transl Vis Sci Technol. 2022 Oct 3;11(10):37. doi: 10.1167/tvst.11.10.37. PMID: 36301553; PMCID: PMC9624268. 5: Ardissino G, Capone V, Tedeschi S, Porcaro L, Cugno M. Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy. Pharmaceuticals (Basel). 2022 Jul 9;15(7):845. doi: 10.3390/ph15070845. PMID: 35890144; PMCID: PMC9325021. 6: Fattizzo B, Motta I. Rise of the planet of rare anemias: An update on emerging treatment strategies. Front Med (Lausanne). 2023 Jan 9;9:1097426. doi: 10.3389/fmed.2022.1097426. PMID: 36698833; PMCID: PMC9868867. 7: Wiles JA, Galvan MD, Podos SD, Geffner M, Huang M. Discovery and Development of the Oral Complement Factor D Inhibitor Danicopan (ACH-4471). Curr Med Chem. 2020;27(25):4165-4180. doi: 10.2174/0929867326666191001130342. PMID: 31573880. 8: Podos SD, Trachtman H, Appel GB, Bomback AS, Dixon BP, Wetzels JFM, Cook HT, Parikh SV, Pickering MC, Tumlin J, Langman CB, Lightstone L, Sperati CJ, Daina E, Bouman KP, Rice K, Thanassi JA, Huang M, Nester C, Remuzzi G. Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan. Am J Nephrol. 2022;53(10):675-686. doi: 10.1159/000527166. Epub 2022 Nov 18. PMID: 36404708. 9: Nishimura JI. [Novel anti-complement therapeutics for hemolytic anemia]. Rinsho Ketsueki. 2023;64(6):466-473. Japanese. doi: 10.11406/rinketsu.64.466. PMID: 37407469. 10: Syed S, Khan R, Khurram F, Khan FH, Safi D, Safi SUD. Treatment of eculizumab refractory paroxysmal nocturnal hemoglobinuria: A systematic review about current treatment options and future direction. SAGE Open Med. 2023 Jun 22;11:20503121231181267. doi: 10.1177/20503121231181267. PMID: 37388903; PMCID: PMC10302528. 11: Rahmati Nezhad P, Riihilä P, Knuutila JS, Viiklepp K, Peltonen S, Kallajoki M, Meri S, Nissinen L, Kähäri VM. Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma. Cancers (Basel). 2022 Jan 8;14(2):305. doi: 10.3390/cancers14020305. PMID: 35053469; PMCID: PMC8773783. 12: Aradottir SS, Kristoffersson AC, Roumenina LT, Bjerre A, Kashioulis P, Palsson R, Karpman D. Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis. Front Immunol. 2021 Jun 10;12:690821. doi: 10.3389/fimmu.2021.690821. PMID: 34177949; PMCID: PMC8222914. 13: Begum F, Khan N, Boisclair S, Malieckal DA, Chitty D. Complement Inhibitors in the Management of Complement-Mediated Hemolytic Uremic Syndrome and Paroxysmal Nocturnal Hemoglobinuria. Am J Ther. 2023 May 1;30(3):e209-e219. doi: 10.1097/MJT.0000000000001609. PMID: 37104648.