Iptacopan  (Synonyms: LNP023)

Iptacopan (LNP023) is a first-in-class, orally bioavailable, highly potent and highly selective factor B inhibitor with an IC₅₀ value of 10 nM. Iptacopan shows direct, reversible, and high-affinity binding to human factor B with a K_D of 7.9 nM. Iptacopan targets the underlying cause of complement 3 glomerulopathy (C3G)^[1][2].

KD: 7.9 nM (factor B)^[2]
IC50: 10 nM (factor B)^[2]

Iptacopan (LNP023) demonstrates potent inhibition of alternative complement pathway (AP)-induced membrane attack complex (MAC) formation in 50% human serum (IC₅₀ value of 130 nM)^[2].
? Iptacopan (LNP023) exhibits excellent selectivity over other proteases affording IC₅₀ values of >30 μM across a panel of 41 human proteases, including the AP protein factor D (>100 μM)^[3].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Iptacopan (LNP023; 20-180 mg/kg; oral administration) prevents KRN (150 μL)-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats^[2].
? LNP023 exhibits moderate half-lives (T_1/2; Wistar Han rats 3.4 h, beagle dogs 5.5 h) and C_max (Wistar Han rats 410 nM, beagle dogs 2200 nM) following oral administration (rat 30 and, dog 10 mg/kg)^[3].
? Iptacopan exhibits terminal elimination half-lives (T_1/2; Wistar Han rats 7 h, beagle dogs 5.6 h) due to high plasma clearance (8, and 2 mL/min/kg respectively combined with large volumes of distribution (2.3, and 0.6 L/kg respectively) following intravenous administration (rat 1.0 and, dog 0.1 mg/kg)^[3].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

422.52

Solid

C₂₅H₃₀N₂O₄

1644670-37-0

O=C(O)C1=CC=C([C@H]2N(CC3=C(OC)C=C(C)C4=C3C=CN4)CC[C@H](OCC)C2)C=C1

Room temperature in continental US; may vary elsewhere.

• [1]. Dimitrios C Mastellos, et al. Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Semin Hematol. 2018 Jul;55(3):167-175.  [Content Brief]

  [2]. Anna Schubart, et al. Small-molecule Factor B Inhibitor for the Treatment of Complement-Mediated Diseases. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931.  [Content Brief]

  [3]. Nello Mainolfi, et al. Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases. J Med Chem. 2020 Jun 11;63(11):5697-5722.  [Content Brief]