New Drug Approvals - Pt. XV - Asenapine (Saphris)

On the 14th August 2009 Asenapine (tradename Saphris) was approved for the acute treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. This class of psychiatric diseases are complex and carry a significant economic healthcare burden; approximately 24 million people worldwide are believed to suffer from schizophrenia, while ca. 67 million people are thought to suffer from bipolar I disorder. Asenapine (previously known by the research code Org-5222) is the one of a large class of drugs aimed at treating such diseases, and shows the typical broad spectrum of against a variety of receptor targets and a complicated mechanism of action, although such drugs are thought to primarily act through antagonism of D2 and 5HT2A receptors. To give some idea of the promiscuity (or polypharmacology) of Asenapine at various aminergic GPCRs, reported pKis are 5HT1A 8.6, 5HT1B 8.4, 5HT2A 10.2, 5HT2B 9.8, 5HT2C 10.5, 5HT5A 8.8, 5HT6 9.5, 5HT7 9.9, alpha1 8.9, alpha2A 8.9, alpha2B 9.5, alpha2C 8.9, D1 8.9, D2 8.9, D3 9.4, D4 9.0, H1 9.0, and H2 8.2. Asenapine has had quite a complex development and commercial history, as web searches will readily show.

Asenapine is a small molecule drug (Molecular Weight of 285.8 g.mol-1 for Asenapine itself, and 401.84 g.mol-1 for the Asenapine Malate dosed ingredient). Asenapine is reasonably absorbed with an absolute bioavailability of 35% for sublingual dosing - for oral dosing (i.e. the drug makes it into the stomach and bowel absorption is far lower at ca. 2%. (This route of absorption also is really 'topical', even through thr drug is orally dosed, hence the topical icon above - confusing -eh?). Asenapine has high plasma protein binding (~95%), and a volume of distribution of 20-25 L.kg-1). It also has a high clearance - 52 L.hr-1. Asenapine is primarily metabolized by oxidative metabolism by CYP1A2 and also by direct glucoronidation by UGT1A4, and is cleared by both renal and hepatic routes in approximately similar proportions. It has a an elimination half-life of ca. 24 hours and due to this long half-life, steady-state plasma concentrations are reached after approximately three days. Recommended dosage is one tablet of 5 mg twice daily (equivalent to ca. 24.9 µmol). The full prescribing information can be found here.

Asenapine has a boxed warning.

The Asenapine structure is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole - and more broadly is member of a set of molecules called dibenzo-oxepino pyrroles. It is fully rule-of-five-compliant. The structure is reasonably unremarkable in terms of its functional group content - the only distinctive feature is the basic amine, but other than being primarily flat, highly rigid and planar, it is difficult to highlight anything more specific.

Asenapine canonical SMILES: CN1CC2C(C1)C3=C(C=CC(=C3)Cl)OC4=CC=CC=C24 Asenapine InChI: InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17) 15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m1/s1 Asenapine InChIKey: VSWBSWWIRNCQIJ-HUUCEWRRSA-N Asenapine CAS registry: 65576-45-6 Asenapine ChemDraw: Asenapine.cdx

The license holder for Asenapine is Schering Plough and the product website is www.saphris.com.