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


Posted by kinasepro on October 10, 2006

Hi Merck KgAa,

Yours is another one of those patent applications that has Kinaspro thinking “this has got to be covered somewhere, by someone”

So did Bayer/Onyx not exemplify the N-Me Carboxamide in their earlier work?

Derek Lowe-
Wont’ ya Go-

and… umm… well… Maybe you could just walk down the hall and poke someone in the eye for me?

No, I guess there’s no need for that, they did indeed claim a handful of disubstituted pryazoles. (RAF: WO199932106, WO199932110, WO199932111, and TrkA WO2005110994), Seems to Kinasepro that these partygoers are a few years late particularly when Merck is doing what Bayer did back in 1999, and BI did first with BIRB796 and then also later with (US6492529), hell even Kirin Beer has one of these: (WO2002088110)

Wait did someone say Kirin Beer?

So Merck think’s they’ve found a way around the Bayer patent estate, and must have some kind of PK / CYP / Drug-like-property / selectivity bump that’s not obvious. They’ve got something similar going on in: WO2006040056 where they are clearly looking at one-offs of Nexavar. You have to remember these are those Crazy-evil-genius-brilliant-German Merck types…

Hmmm, so what’s new in these patents? Well, one of the claims is on TIE2, and you can tell by the Markush they are only attempting to make very narrow claims around the two Pyrazole substituents. I didn’t translate all the structure names, but it appears there are a number of furans exemplified with a handful of other R group modifications. The one example they draw a structure for:

Of note Deciphera has 2 similar applications which published in July. WO2006071940, and WO2006081034 they are labelled VEGF/PDGF/Bcr-Abl applications

And the companies with advanced Angiogenesis programs that any potential candidate has to beat:

Bayer……… Check (
Pfizer…….. Check (
Astra-Zeneca.. Check (
Genentech….. Check (
Bristol-Myers Squibb, Novartis, Glaxo, Roche, Amgen, Kirin Brewing Company, check, check, checkitty, check, check, check – yah, he did say Kirin Beer.


3 Responses to “DE102005015253”

  1. milkshake said

    BIRB796 is a non-selective p38 alpha+beta+gamma inhibitor that also weakly hits JNK. It binds in a non-typical mode (outside the p38 active site).

    I don’t see how BIRB796 has any bearing on angiogenesis/anti-tumor programs, apart from structural similarity. These are different kinases – and quite likely also different binding modes.

  2. Kinasepro said

    Hi Milkshake,

    Well – BIRB796 is an important molecule as it was the first to describe the DFG-out binding motif (a PDF is linked) The morpholine oxygen binds to the Hinge-NH in the ATP biding region, and the arylurea binds in the same space as Bayer’s Nexavar: In a lipophyllic region that the modelers call H1. In the DFG-out conformation there’s enough space there to poke all the way through the back of the enzyme and out to solvent (aka gleevec)

    All the other diaryl urea kinase inhibitors that KP is aware of bind in a very similar fasion – no matter the kinase.

    A good example is to look at birb: (PDB: 1KV2) and align it to a VEGFR2 inhibitor: (PDB: 1YWN) This is something that can be done for free – using a program like pymol.

    Aligning the whole enzyme shows that the two ligands do indeed bind very similarly. Here’s a quick (and dirty) overlay of BIRB796 and a Boehringer Ingelheim diaryl urea (tie2-vegf inhibitor)

    Looking at enough of these things, one gets the impression that you can dial activity around the kinome with just subtly different functional groups.

  3. milkshake said

    Thank you!

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