InvestorsHub Logo
Followers 22
Posts 1379
Boards Moderated 0
Alias Born 03/31/2017

Re: georgejjl post# 214503

Sunday, 01/28/2018 8:38:57 PM

Sunday, January 28, 2018 8:38:57 PM

Post# of 403325
George, you must be rated as an EXPERT poster? The difference between a "pro" vs. "EXPERT" rated poster is that an "EXPERT" rated poster references source of information with a citation listed within the body of their posts like you do. The "pro" rated posters only give one sentence with little to know substance.

Thank you for posting factual information on this board and being an "EXPERT" poster!

Not long now...

Go Leo and IPIX!


Otezla (Apremilast) is derivative of thalidomide. Younger people should look up thalidomide.

https://en.wikipedia.org/wiki/Development_of_analogs_of_thalidomide

Apremilast:

Development of apremilast[edit]

Figure 4: Molecular structure of apremilast, an analog of thalidomide
After finding a novel set of analogs of thalidomide, namely 3-(1,3-dioxo-1,3 dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl) propionic acid (not shown), which had PDE4 inhibition activity the work began to optimize the activity. For that purpose the researchers used a known structure moiety, 3,4-dialkoxyphenyl, that is a recognized pharmacophore in PDE4 inhibitors such as rolipram (Figure 6) and roflumilast and added it onto the structure of the previously mentioned analog series. After tweaking the structure and testing different substitution at the 4-position of the phthaloyl ring and at the carboxyl acid the researchers finally landed at a molecule that potently inhibits PDE4 and TNF-a, which they later named apremilast (Figure 4). The S-enantiomer of apremilast was chosen since it was the more active enantiomer.[21] Since the structure of apremilast lacks the acidic chiral hydrogen it should not racemize in vivo, unlike thalidomide, lenalidomide and pomalidomide.[42][43]

Structure-activity relationship[edit]

Figure 5: Thalidomide with the ring system outlined
Since the mechanism of action of thalidomide and its analogs is not fully clear and the bioreceptor for these substances has not been identified, the insight into the relationship between the structure and activity of thalidomide and its analogs are mostly derived from molecular modelling and continued research investigation.[43][44] The information on SAR of thalidomide and its analogs is still in process so any trends detailed here are observed during individual studies. Research has mainly focused on improving the TNF-a and PDE4 inhibition of thalidomide,[7][21] as well as the anti-angiogenesis activity.[45][46]

TNF-a inhibitors (not via PDE4)[edit]
Research indicated that a substitution at the phthaloyl ring would increase TNF-a inhibition activity (Figure 5). An amino group substitution was tested at various locations on the phthaloyl ring (C4, C5, C6, C7) of thalidomide and EM-12 (previously described). Amino addition at the C4 location on both thalidomide and EM-12 resulted in much more potent inhibition of TNF-a. This also revealed that the amino group needed to be directly opposite the carbonyl group on the isoindolinone ring system for the most potent activity.[47] These analogs do not inhibit PDE4 and therefore do not act by PDE4 inhibition. Other additions of longer and bigger groups at the C4 and C5 position of the phthaloyl ring system of thalidomide, some with an olefin functionality, have been tested with various results. Increased inhibitory effect, compared to thalidomide, was noticed with the groups that had an oxygen atom attached directly to the C5 or C4 olefin. Iodine and bromine addition at C4 or C5 resulted in equal or decreased activity compared to thalidomide.[48] These groups were not compared with lenalidomide or pomalidomide.

PDE4 inhibitors[edit]

Figure 6: Rolipram, highlighting the 3,4-dialkoxyphenyl moiety

Figure 7: Common structure for PDE4-inhibiting thalidomide analogs
The common structure for analogs that inhibit TNF-a via inhibition of PDE4 is prepared on the basis of hydrolysing the glutarimide ring of thalidomide. These analogs do not have an acidic chiral hydrogen, unlike thalidomide, and would therefore be expected to be chirally stable.[42]

On the phenyl ring, a 3,4-dialkoxyphenyl moiety (Figure 6) is a known pharmacophore in PDE4 inhibitors such as rolipram. Optimal activity is achieved with a methoxy group at the 4-position (X2) and a bigger group, such as cyclopentoxy at the 3-position carbon (X3). However the thalidomide PDE4 inhibitory analogs do not follow the SAR of rolipram analogs directly. For thalidomide analogs, an ethoxy group at X3 and a methoxy group at X2, with X1 being just a hydrogen, gave the highest PDE4 and TNF-a inhibition.[21] Substitutes larger than diethoxy at the X2–X3 position had decreased activity. The effects of these substitutions seem to be mediated by steric effects.[42]

For the Y-position, a number of groups have been explored. Substituted amides that were larger than methylamide (CONHCH3) decrease PDE4 inhibition activity.[42] Using a carboxylic acid as a starting point, an amide group has similar PDE4 inhibition activity but both groups were shown to be a considerably less potent than a methyl ester group, which had about six-fold increase in PDE4 inhibitory activity. Sulfone group had similar PDE4 inhibition as the methyl ester group. The best PDE4 inhibition was observed when a nitrile group was attached, which has 32 times more PDE4 inhibitory activity than the carboxyl acid.[21] Substituents at Y leading to increasing PDE4 inhibitory activity thus followed the order:

COOH ≤ CONH2 ≤ COOCH3 ≤ SO2CH3 < CN
Substitutions on the phthaloyl ring have been explored and it was noticed that nitro groups at the C4 or C5 location decreased activity but C4 or C5 amino substitution increased it dramatically.[42] When the substitution at the 4 (Z) location on the phthaloyl ring was examined, hydroxyl and methoxy groups seem to make the analog a less potent PDE4 inhibitor. An increase in activity was observed with amino and dimethylamino to a similar extent but a methyl group improved the activity further than the aforementioned groups. A 4-N-acetylamino group had slightly lower PDE4 inhibitory activity, compared with the methyl group, but increased the compound's TNF-a inhibitory activity to a further extent.[21] Substituents at Z leading to increasing PDE4 inhibitory activity thus followed the order:

N(CH3)2 ≤ NH2 < NHC(O)CH3 < CH3

Thalidomide:

https://en.wikipedia.org/wiki/Thalidomide

Good luck and GOD bless,

George


Volume:
Day Range:
Bid:
Ask:
Last Trade Time:
Total Trades:
  • 1D
  • 1M
  • 3M
  • 6M
  • 1Y
  • 5Y
Recent IPIX News