Kinase Chemistry – Just a year and a half behind the times.


Posted by kinasepro on October 21, 2006

Hey Rigel, SYK prodrugs eh? I see you guys have been on this stuff like white on rice for a couple years. I suppose Kinasepro could wait for the Biorg. Med. Chem. Lett. to come out some time in 2010, but I’m gonna see if I couldn’t kick up a first draft to help you guys out. Here Goes:

So R112 sucks but since we’ve got this really cool assay and Pfizer’s had a bag of cash dangling out there for us, its not like we were just going to give up on the target. Yah in case you were wondering we all lost a ton of money back then.

Anyhow the early SAR for this project was carved around the arylaminopyrimidine scaffold based on a library hit, and and we put the kitchen sink both meta and para on the pyrimidine (WO2003063794 – 7/8/03; WO2004014382 – 2/19/04).

R112 had crummy solubility, so we thought the idea of shoving it up peoples noses sounded pretty good. You know, like an allergy indication – something sort of topical where you might get away without solubility? Put it together with some of the finest, and most advanced dispersal agents known to mankind and throw it into a few hundred sneezing folks and lets see what happens. Somehow it didn’t work out. Go figure, thats just how these things go sometimes I guess.But as I was saying, some of our best early compounds were bicycles(1), and since I had some luck with indoles on a previous project I really put a beat down on that indazole, and indole chemistry. C’mon they’re supposed to be phenol bioisosteres. It just wasn’t working out until we started making benzoxazines (2) and then we knew: these comopounds are for real!


That brings me to these second generation analogs where we got a feel for the SAR. Along the road we learned a few things: Namely as we honed in on the benzoxazines we found that the saturated ring preferred a hindered center next to oxygen (4), that the other aryl was more or less solvent exposed, and that we could get away with putting tons of stuff out there (3). Oh yah – and that an azabenzoxazine improved our drug like properties (5). Sure they were harder to make, but you gotta do what you gotta do, eh? The pyrimidine wouldn’t budge, but oh yah, we did find some success with a few non-benzoxazines (WO2005013996). We had a handful of non-benzoxazines, but they just didn’t cut it. Insoluble as it is R406 was the best of the lot.

r406-We nominated the benzenesulfonic acid salt, and the phase 1 study was done around the same time as our Phase II for R112. This compound is oral and we proved we were hitting a biomarker but for some reason the stock didn’t go back up =<

r3To polish off this project we looked at some phosphonate prodrugs which eventually led to R788 (6), but pretty much everybody is on HCV now. US20060234983 published Thursday, and WO2006078846 came out back in January – they’re all a part of this work. The non-prodrug aza-analog of R406 had a solubility of like 1 ug / mL – while the phosphonate is like *POW* 5 mg/mL, it also gives us us a %f of about 30%. Oh, and R788 rox k thx.** The above is merely a lighthearted satirical dramatization derived from Kinasepro’s keen ability to filter the patent literature and press releases. Please feel free to complain in the comments or to

>> Updated 10/23 >> Fixed a couple chemdraw errors, and would like to add a reader submission link to an article on R406 from August ’06 (free link). They got an xray but the picture… well the picture leaves something to be desired.


4 Responses to “US20060234983”

  1. JC said

    Ha ha.

    You overlooked US20060167254

  2. milkshake said

    The problem with the prodrug is that hydroxymethyl-modified amides are fairly stable – I would like to see the rate of productive hydrolysis of the hydroxymethyl amide intermediate compared to its clearance rate.

  3. kinasepro said

    Hey Milkshake, glad your back.

    In US20060234983 and the WO – they actually give a remarkable amount of data on the rat preclinical stuff for R406 and the prodrug. Suggests that Pfizer most certainly passed, and now they have to shop it around.

    >> link to picture for PK >>

    On the prodrug strategy – a BMS application recently published (US20060047135; March ’06) on a process route to making the chloromethylene intermediate of these types of prodrugs… If its viable… well I guess we’ll see.

  4. eladito said

    Maybe I’m missing something here, but I thought the published results for R406 orally were quite strong. I will be happy to hear of any available alternatives…

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