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June 22, 2009
Funky Carbocycles
Posted by Derek
Earlier this month I posted about rolofylline, which I noted has a rather unusual noradamantane attached to it. Now check out this ORL-1 compound from Banyu, complete with the not-so-widely-heard-of bicycloheptane-spirocyclopropane group.
This was not arrived at lightly, as you'd imagine. There's a table in the Supporting information for the paper, but I'll quote from the body of the main manuscript:
Various kinds of cycloalkanes, substituted or nonsubstituted cyclopropyl rings to medium sized rings (such as cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl), spiroalkane (such as spiro[2.5]octanemethyl, spiro[3.5]nonanemethyl, spiro[4.5]decanemethyl, spiro[2.4]heptanemethyl, spiro[3.4]octanemethyl, spiro[4.4]nonanemethyl), bicycloheptane (such as methylbicyclo[2.2.1]heptylmethyl, dimethylbicyclo[2.2.1]heptylmethyl, spirocyclopropanebicycloheptanemethyl), and branched alkanes (such as 3,3-dimethylbutane, 3,3-dithylbutane, 1-methylcyclobutaneethyl, 1-methylcyclopentaneethyl, 1-methylcyclohexaneethyl) were tested.
No, that couldn't have been a lot of fun. Anyone else out there found themselves having to optimize grease recently?
Comments (5)
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1. Igor on June 22, 2009 10:20 AM writes...
Sadly it seems that many of us in med chem tend to spend way too much time optimizing grease.
I have never worked in the CNS area, but it appears to me that many of the successful modulators are of the small MW variety with some grease, a tertiary basic group, and some other spinach.
So, it appears that many times the space available for novelty becomes some new variant of the greasy portion, although I have seem some pretty funky piperidine/piperazine surrogates. I would expect the Banyu guys may have just killed two birds with one stone in this case, activity and patentability.
Derek, since you have some experience in this area, are my observations correct or skewed?
Permalink to Comment2. Norepi on June 22, 2009 4:11 PM writes...
It seems that another place grease optimization comes up is in some of the steroid mimics that inhibit the various metabolic steroid-processing enzymes (where there are large hydrophobic cavities). I remember Merck's candidate (I believe it was called Compound 544), for inhibition of 11-beta hydroxysteroid dehydrogenase was one of a large class of adamantyl triazoles They arrived at this structure after going through a long series of bulkier carbocycles and various things like cyclooctane, with adamantyl becoming a case of The Only Thing That Works There.
Permalink to Comment3. Zak on June 22, 2009 7:42 PM writes...
Wonder if the fact that they are both from Japan is relevant?
Permalink to Comment4. drug_hunter on June 22, 2009 9:27 PM writes...
There seems to be something about unusual aliphatic polycyclic hydrocarbons - they are sometimes far more stable to metabolic oxidation than I would have guessed they'd be. I haven't seen any good explanation for the "rules" that govern this behavior - anyone have any good references or ideas?
Permalink to Comment5. chupvl on July 16, 2009 4:21 AM writes...
the question is to fill the grease gap or fill the binding site tightly? The structure of ORL1 can be modeled but not discussed in the article (pity).
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