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Tuesday, 9 November 2010

2010 New Drug Approvals - Pt. XV - Lurasidone (Latuda)



ATC code (partial): N05AE


On October 28th 2010, the FDA approved Lurasidone (Tradename:Latuda) (Lurasidone is also known by the research code SM-13,496). Lurasidone is an atypical antipsychotic agent indicated for the treatment schizophrenia.

Lurasidone displays broad polypharmacology against a wide range of rhodopsin-like aminergic GPCRs, acting as an antagonist with high affinity at dopamine D2 receptors (Uniprot: P14416, ChEMBL: 72) (Ki of 1 nM), serotonin 5-HT2A (Uniprot: P28223, ChEMBL: 107) (Ki of 0.47 nM) and 5-HT7 receptors (Uniprot: P34969, ChEMBL: 10209) (Ki of 0.49 nM), and with moderate affinity at alpha-2C adrenergic receptors (Uniprot: P18825, ChEMBL: 218) (Ki of 10.8 nM) and at alpha-2A adrenergic receptors (Uniprot: P08913, ChEMBL: 52) (Ki of 40.7 nM). Lurasidone acts also as a partial agonist at serotonin 5-HT1A receptors (Uniprot: P08908, ChEMBL: 51) (Ki of 6.4 nM) and exhibits little or no affinity for histamine H1 (Uniprot: P35367, ChEMBL: 127) and muscarinic M1 receptors (Uniprot: P11229, ChEMBL: 61) (IC50 > 1000 nM and IC50 > 1000 nM, respectively). The efficacy of Luasidone is thought to be primarily related to the D2 and 5HT2A antagonism. All atypical antipsychotics display this complex polypharmacology.

Lurasidone is a synthetic small-molecule drug (Molecular Weight of 492.7 g/mol for Lurasidone itself and 529.14 g.mol-1 for the dosed HCl salt), is fully Rule-of-Five compliant, lipophilic and very slightly soluble in water.

Lurasidone has low systemic bioavailability (9-19%), and a high volume of distribution of 6173L, and displays high plasma protein binding (ppb) of ~99%. The half life is 18 hours, and steady-state plasma levels are reached 7 days after starting regular dosing. Lurasidone is predominantly metabolized by CYP3A4 into four major metabolites (two active metabolites and two 'inactive') - metabolites include hydroxylation of the nornbornane ring, N-dealkylation and S-oxidation. The apparent clearance is 3902mL/min, with the bulk of the drug being excreted in the feces. Dosage is oral, with a recommended starting dosage is 40 mg once daily (equivalent to 81umol), with a recommended maximum dosage of 80 mg daily.


Lurasidone is a chiral benzoisothiazol derivative - the benzoisothiazol is the fused five-six dual ring structure on the right of the figure above. Its structure (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione contains an imide heterocyclic and a piperazine functional group. The central piperazine nitrogen is basic. The chemical structure, properties and pharmacology are similar to Ziprasidone (Trademark:Geodon).

NAME="Lurasidone"
TRADEMARK_NAME="Latuda"
ATC_code= NA
SMILES="O=C1C2[C@@H]3CC[C@@H](C3)C2C(=O)N1C[C@@H]4CCCC[C@H]4CN5CCN(CC5)c6nsc7ccccc67"
InChI="InChI=1S/C28H36N4O2S/c33-27-24-18-9-10-19(15-18)25(24)28(34)32(27)17-21-6-2-1-5-20(21)16-30-11-13-31(14-12-30)26-22-7-3-4-8-23(22)35-29-26/h3-4,7-8,18-21,24-25H,1-2,5-6,9-17H2/t18-,19+,20-,21-,24?,25?/m0/s1"
ChemDraw=Lurasidone.cdx

The full prescribing information can be found here.

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

The license holder is Sunovion Pharmaceuticals Inc. and the product website is www.latuda.com

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