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Thursday, 20 January 2011

New Drug Approvals 2011 - Pt. I Spinosad (NatrobaTM)

partial ATC code: P03A

The first FDA new drug approval of 2011 is Spinosad, approved on Jan 18th 2011 (NDA 022408). Spinosad (tradename: Natroba) is a pediculicide, indicated for the topical treatment of head lice (the parasitic insect Pediculus humanus capitis) infestations in patients aged over four years of. One gram of Natroba contains 9 mg of Spinosad as a viscous suspension.

Spinosad has a unique mode of action that is different from all other known pediculicides. Spinosad causes excitation of the insect nervous system, leading to involuntary muscle contractions, prostration tremors and finally paralysis and death. These effects are similar to those associated with the activation of nicotinic acetylcholine receptors (nAChRs), and there is evidence that insect nAChRs are involved in the mechanism of action of spinosyn A and D (two active components of Spinosad) a representative nAChR for a target species is Drosophila melanogaster nAChR Dalpha6 (UniProt:Q86MN8).  nAChRs are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction. These receptors are triggered by the binding of the neurotransmitter acetylcholine and their stimulation causes muscular contraction. This protein family is structurally related to the significant family of human drug targets - the ligand-gated ion channels, in which drugs bind at extracellular sites in the so-called ligand-binding domain (Pfam:PF02931).

Spinosad has already been used for a number of years as an oral anti-flea medication for pets and also to control a variety of insect pests, such as fruit flies, caterpillars, spider mites, fire ants; and has now received approval as a prescription human medication. Since it does not significantly affect beneficial insects and predatory mites, Spinosad is actually recommended for use in an integrated pest management program for commercial greenhouses. Spinosad is the first head lice treatment that does not require combing and it has been shown to be more effective in eliminating head lice than previously approved treatments. These include both natural and synthetic products, such as Malathion 0.5% (tradename: Ovide), Permethrin 1% (tradename: Nix), Pyrethrins (tradename: Rid) and the recently approved Benzyl Alcohol 5% (tradename: Ulesfia; approved in 2009). 

Spinosad, the active ingredient, is derived from the fermentation of a naturally occurring soil dwelling bacterium called Saccharopolyspora spinosa, a rare actinomycete collected on a Caribean island in 1982. Spinosad is a mixture of the natural products spinosyn A and spinosyn D in a ratio of approximately 5 to 1.

Spinosyn A (IUPAC: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5- (dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-methyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranoside; INCHIKEY: SRJQTHAZUNRMPR-UYQKXTDMBW; SMILES: [H][C@@]12C[C@H](C[C@@]1([H])[C@]1([H])C=C3C(=O)[C@H](C)[C@H](CCC[C@H](CC)OC(=O)C[C@@]3([H])[C@]1([H])C=C2)O[C@H]1CC[C@@H]([C@@H](C)O1)N(C)C)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC; ChEMBL: CHEMBL501411; ChEBI: CHEBI:9230; PubChem: CID115003; ChemSpider: 391358) has a molecular weight of 731.96 Da, no hydrogen bond donors, eleven hydrogen bond acceptors, a calculated logP of 4.9 and a polar surface area of 111 Å2. Spinosyn D differs from Spinosyn A, having one more methyl group at the double bond carbon of the cyclohexene of the indacene derived central moiety. Thus, Spinosyn D (IUPAC: (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranoside; INCHIKEY: RDECBWLKMPEKPM-PSCJHHPTBK; SMILES: [H][C@@]12C[C@H](C[C@@]1([H])[C@]1([H])C=C3C(=O)[C@H](C)[C@H](CCC[C@H](CC)OC(=O)C[C@@]3([H])[C@]1([H])C=C2C)O[C@H]1CC[C@@H]([C@@H](C)O1)N(C)C)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC; ChEMBL: CHEMBL503450; ChEBI: CHEBI:9232; PubChem: CID183094; ChemSpider: 159214) has a molecular weight of 745.98 Da, and, like Spinosyn A, has no hydrogen bond donors, eleven hydrogen bond acceptors, a calculated logP of 4.8 and a polar surface area of 111 Å2. Both Spinosyn A and B fail the rule of five. A notable feature of both spinosyn structures is the tertiary amine, which will be protonated under physiological conditions and the relatively small macrolide (in this case a 12-membered cyclic lactone) ring fused to the rigid and lipophilic 5:6:5 ring system. Many natural products contain a macrolide ring.

The full US prescribing information can be found here. The license holder is ParaPRO LLC and the product website is

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