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The Tail’s The Thing – Alkylamine Ethers and Zafgen’s ZGN-433

While posting about the Zafgen obesity drug candidate yesterday, I was staring at the Markush structure we’d drawn for ZGN-433 when Carmen Drahl sent over a 2008 volume of the World Health Organization International Nonproprietary Names (INN) list, a collection of proposed or recommended non-proprietary names and structures for currently-marketed drugs or drug candidates in clinical trials. I glanced down the list to find beloranib, the common name for ZGN-433, and I realized immediately . . . it had the “tail!”

The “tail” nickname should probably be called an (N,N-dimethylamino)ethyl ether functional group. It’s one of the specific atomic arrangements medicinal chemists tack onto lead molecules to improve potency, resist metabolic oxidation, etc. This is one of the more popular groups, it seems, perhaps what someone in catalysis or biochemistry might call a “privileged structure,” a molecular motif that so perfectly accomplishes a given task that it pops up in many different places.

Marketed drugs that riff on this pharmacophore include: Tamoxifen (breast cancer), Benadryl (aka diphenylhydramine, an antihistamine), Dimazole (antifungal), Amiodarone (antiarrhythmic), Gallamine (muscle relaxant), and Evista (estrogen uptake modulator). In Nefopam (an analgesic), the motif is even found embedded in an 8-membered ring, admittedly not the first thing one might think to synthesize – it’s usually harder to make these “medium-ring” compounds  than their 5- or 6-membered counterparts.

In the case of beloranib, one could imagine three roles for the alkylamine ether group. It could serve as an isostere, a group that mimics the space-filling and electronic properties of another, standing in for amino-alkyl side chains found in bioactive plant metabolites like psilocybin or tryptamine. It might also be useful to increase solubility of the drug, which makes dosing easier and improves the drug’s ability to reach the bloodstream when taken orally (Note: this may not have worked for beloranib, since the drug is currently administered by sub-Q injection). A more likely explanation might be the well-established phenomenon of “tuned” basic nitrogens that hydrogen bond with acidic residues in enzyme active sites, increasing binding free energy (better inhibition) – see this 1982 paper by John Katzenellenbogen (U.Illinois) for basicity tuning in Tamoxifen analogues.

We hope Haystack readers will weigh in on what they think the “tail” is accomplishing for ZGN-433. Yesterday’s Zafgen post has already generated some thoughtful commentary via Twitter from John LaMattina, former Senior Vice President, Pfizer Inc and President, Pfizer Global Research and Development:

John_LaMattina: @lisamjarvis Hard to get excited about a compund that acts by a mystery mech. with epoxide moieties. FDA will justifably want long-term tox.

We here at the Haystack would like to thank Dr. LaMattina for his input.

6 Comments

  • Jul 13th 201115:07
    by Chemjobber

    I vote for metabolic stability — is it a coincidence that they’re all on phenolic alcohols (other than it’s a handy place to alkylate?)

  • Jul 13th 201115:07
    by See Arr Oh

    @Chemjobber – While I’m tempted to say yes, there’s a few examples (doxylamine, deramciclane, clofenciclan) where the “tail” is connected to tertiary alcohols, albeit at benzylic positions…

  • Jul 13th 201120:07
    by T

    Two epoxides? A Michael accepting enone?

    This molecule will nuke every nucleophile in your body.

    No way will the FDA ever let this molecule be administered chronically.

  • Jul 14th 201110:07
    by See Arr Oh

    @T – While it’s a valid point (and the molecule hasn’t been advanced to large-scale human trials yet), the idea springs from two known natural products, fumagillin and ovalicin. In France, fumagillin, at least, has been granted orphan drug status (Sanofi-Aventis) for the treatment of intestinal microsporidial infection.

  • Jul 14th 201115:07
    by Curious Wavefunction

    I vote for improved solubility through the addition of a polar group; without the tail the molecule would be pretty lipophilic. They had used a similar strategy for improving solubility and cell permeability for some of the early HIV protease inhibitors.

  • Pingback

    Mar 21st 201322:03
    by VVUS: Hey, Wha’ Happened? | Pi Shaped

    [...] of fumagillin analogs.  The two epoxide rings seem to be critical for MetAP2 inhibition, and the (N,N-dimethylamino) ethyl ether moiety seems to be a popular functional group that may improve potency and resist metabolic oxidation. [...]

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