Which example in patent WO2015009616A1 corresponds to Iptacopan (LNP023)?

Iptacopan (LNP023) corresponds to Example-20a (free acid) and Example-20c (phosphate salt) in patent WO2015009616A1. It is the (2S,4R)-enantiomer of 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-methylpiperidin-2-yl)benzoic acid with molecular formula C₂₄H₂₈N₂O₃ and MW 392.49 g/mol.

What is the IC₅₀ of Iptacopan (Example-20a) against Factor B?

Iptacopan (Example-20a) achieves a TR-FRET assay IC₅₀ of 0.009 μM against Factor B, making it one of the most potent compounds in the entire patent series. Its (2R,4S)-enantiomer (Example-20b) has an IC₅₀ of 0.29 μM — 32-fold less potent.

Why is the free carboxylic acid essential in Iptacopan's structure?

The free carboxylic acid forms critical ionic and hydrogen-bonding interactions with Factor B. Replacing it with an amide (IC₅₀ = 11 μM), nitrile (IC₅₀ >100 μM), or methyl ester (IC₅₀ = 1.7 μM) results in potency losses exceeding 1,000-fold, confirming the acid group is non-negotiable for high-affinity binding.

How does the piperidine scaffold compare to pyrrolidine analogs in this patent?

Piperidine analogs are 10–100× more potent than corresponding pyrrolidine analogs. The 6-membered piperidine ring adopts a chair conformation that projects the 4-methyl group into a hydrophobic subpocket with optimal geometry. Pyrrolidine's 5-membered envelope conformation cannot replicate this spatial arrangement, reducing binding affinity.

What role does the 5-methoxy group on the indole play in Factor B binding?

The 5-methoxy group is optimal for Factor B potency, acting as a hydrogen-bond acceptor and providing a balanced lipophilic contribution. Replacing 5-methoxy with 5-methyl (Example-25a) increases IC₅₀ from 0.009 μM to 15 μM — a 1,667-fold potency loss — confirming the critical role of this substituent.

What is the clinical formulation strategy for Iptacopan described in WO2015009616A1?

The patent describes Example-20c as the phosphate salt of Iptacopan, prepared by controlled crystallization from acetonitrile/methanol. The crystalline phosphate salt offers enhanced aqueous solubility, consistent manufacturing via defined polymorph, improved dissolution rate, and long-term solid-state stability for oral tablet formulation.