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The SARfaris: GPCR, Kinase, ADME

Monday, 6 July 2009

New Drug Approvals - Pt. VIII - Iloperidone (Fanapt)

Another drug onto the market this year is Iloperidone (USAN) marketed as Fanapt, which was approved on May 6th. Iloperidone is an antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone displays broad polypharmacology, acting as an antagonist at dopamine D2 (Ki of 6.3 nM) and dopamine D3 (Ki of 7.1 nM), serotonin 5-HT2A (Ki of 5.6 nM), dopamine D4 (Ki 25 nM), 5HT6 (Ki of 43 nM), 5HT7 (Ki of 22 nM) and alpha-1 adrenergic receptor (Ki of 36nM) (phew!) and belongs to the general class of atypical antipsychotics. Lower affinities, but also probably relavent for the clinical pharmacology, are observed at the 5HT1A, D1 and H1 receptors). Iloperidone is a small molecule drug (Molecular Weight of 426.5 g.mol-1), is fully Rule-of-Five compliant, lipophilic and pratically insoluble in water and has good oral absorption (96% bioavailable). Iloperidone has a plasma half-life of 18 hours, a volume of distribution of 1,340-2,800L and plasma protein binding of ~95%.

Iloperidone elimination is mainly through CYP dependent hepatic metabolism (specifically CYP3A4 and CYP2D6); some of these metabolites are themselves pharmacologically active. CYP2D6 is an example of a genetically variable gene, with a fraction of the population having a form of the gene that is significantly less active - so called 'slow metabolizers', this generally leads to variability of drug response. Iloperidone has an apparent clearance of 47-102 L/hour, with the bulk of the clearance being renal (i.e.. the drug is excreted in the urine). The recommended dosage is 12 to 24 mg/day administrated twice daily (equivalent to ca. 28-56uM). Like many drugs of this class, there are a broad range of potential adverse events, including a propensity for the compound to increase QTc interval. The full prescribing information can be found here.

Iloperidone has a boxed warning (colloquially known as a 'black box').

Iloperidone belongs to the chemical class of piperidinyl-benzisoxazole derivatives - the piperidine in the six membered ring containing the nitrogen in the middle of the molecule, while the benzisoxazole is the fused five-six dual ring structure at the bottom left. Its structure 4'-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone contains a tertiary amine which makes the molecule basic, but otherwise the molecule is largely lipophilic in character. A relatively unusual chemical feature for a drug is the presence of the aryl-ketone group.

Iloperidone canonical SMILES: O=C(c4ccc(OCCCN3CCC(c2noc1cc(F)ccc12)CC3)c(OC)c4)C Iloperidone InChI: InChI=1/C24H27FN2O4/c1-16(28)18-4-7-21(23(14-18)29-2)30-13-3-10-2 7-11-8-17(9-12-27)24-20-6-5-19(25)15-22(20)31-26-24/h4-7,14-15,17 H,3,8-13H2,1-2H3 Iloperidone InChIKey: XMXHEBAFVSFQEX-UHFFFAOYAT Iloperidone CAS registry: 133454-47-4 Iloperidone ChemDraw: Iloperidone.cdx

The license holder for Iloperidone is Vanda Pharmaceuticals and the product website is

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