Skip to main content

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 www.natroba.com.

Comments

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site:   https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29 .  Please see ChEMBL_29 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29/chembl_29_release_notes.txt New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no