KinasePro

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

JNJ-38877605

Posted by kinasepro on May 8, 2009

Still in the clinic:  It’s JnJ’s ph1 c-Met inhibitor.

FC(C1=NN=C2N1N=C(C3=CN(C)N=C3)C=C2)(C4=CC5=C(N=CC=C5)C=C4)F

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16 Responses to “JNJ-38877605”

  1. spuddo said

    no metabolite crystals in the kidney?

  2. milkshake said

    They got the CF2 there – that benzylic methylene was always the site in the Sugen original compounds that got hydroxylated. I bet the diaryl thio ether turned to sulfone and thats what crashed out in the kidneys.

  3. Orgmed said

    Where is the diaryl thio ether in this molecule?.

  4. Orgmed said

    Any Idea who first identified this series as c-Met inhibitor. SGX or JNJ?.
    SGX-523 registered for Phase I: In January 2008.
    JNJ registered for Phase I: In March 2008.
    The idea of -CF2 in JNJ seems like after SGX-523?.
    I am not sure the priority dates in their patent.

  5. milkshake said

    thioether is in the SGX compounds, hence the metabolism and kidney crystals. Both SGX and JNJ compounds are closely based on the old Sugen patents, see the discussion below the SGX compound fews days before.

    • kinasepro said

      I believe Vertex described the first use of this motif for PIM/GSK3/SRC etc: WO/2004/058769. Shortly thereafter the Sugen series describes the phenols for c-Met: WO/2005/004607 & WO/2005/010005

      Then came the phenol isosteres from JnJ: WO/2007/075567; Vertex: WO/2007/064797; then SGX nearly a year later with WO/2008/051805 & WO/2008/051808

      So J&J was actually first. SGX has a number of carbon linked molecules in the WO/2008/051805 application, but the earliest priority date gets spanked by nearly a year thanks to WO/2007/064797. I suppose it could come down to notebooks, but prior to these apps SGX was working mostly on the aza-indoles.

      In all of this the take home message for me is that (1) Pfizer could have been there 2 years before everybody else if they hadn’t made Sugen go away~ & (2) KP had the structure of the JnJ candidate 2 days after the first patent application published & almost a full year before they first released the structure at the ’08 AACR. So There!

  6. milkshake said

    There was actually a longer history if you go to Sugen patents. There was the acylated isatine hydrazone patent on stuff that came from HTS for c-Met. Based on X-ray co-crystal structure we made the terrible-looking tetracyclic compounds, disconnection of which then provided the triazolotriazines. Vertex patent is coincidental, they were after different targets and if you look at their examples the subststitution pattern is not quite the same.

    I think Pfizer was ahead, and I think they were right not to develop this particular series for cancer because of the mentioned trouble with easy development of resistance. But Pfizer San diego took the other series, which did not have the problem with mutation-based resistance, and they worked on it for awhile half-heartedly. But Agouron folks always wanted to advance their own series and they eventually it was their compound that got chosen to go into clinic.

    • M. Blue said

      Indeed Sugen was the front runner with this scaffold for this target. Considering that there’s only 5 months between Vertex 2004 patent and Sugen’s 2005 patent, Sugen sure did have this discovered independently, as claimed by this author. The same person, almost 2 yrs ago when Vertex and J&J published their patents, had nicely, but implicitly laid out the evolution of the triazolotriazines scaffold.

      In fact, one could even extrapolate the isatin-hydrazones to the original oxindole scaffold from Sugen.

      Pfizer did miss out on this, a la Tarceva.

      • M. Blue said

        Also to be included in this loop is Amgen’s patent WO/2008/008539. I am not sure this was disussed before. Amgen folks also pulished this J. Med. Chem. with a nice x-ray crystal structure in 2008 with this scaffold.

      • milkshake said

        thats what we thought at the time when we hot the HTS isatin-hydrazone hit but the binding mode turned out to be entirely new. Old tyrfosine-derived Sugen oxindole compounds are classic hinge binders. The acylated isatine hydrazones (and the later compounds) bind in a way of the isatine hydrazone (or the el deficient triazolotriazine) being placed perpendicular over the slit of the ATP binding site, like a lid on a pot, with Tyr from the activation loop pi-stacking ontop

  7. Orgmed said

    Thanks Kinasepro and Milkshake for the details on these
    two compounds.
    So the SGX Fragment based/X-ray do not seems any contribution on the innovation side. Its simply a Med.Chem thought by their group based on JNJ?.

    In SGX preclinical model if they use Rabit model (urine is slightly alkaline pH) then they could have confirmed this thioether metabolism and crystal issue, just a thought.

    • kinasepro said

      The discovery at SGX was most likely independant of JnJ, though JnJ did get there first as evidenced by the priority dates. Its also a bit premature to write off the ‘fragment based’ methods – they may have played a role in the choice of a quinoline as a replacement for the phenol, but clearly these series were largely a knowledge based effort relying on the earlier Sugen findings.

  8. Shop said

    How sure are you that it was the thio ether that was metabolized ?….

  9. Shop said

    Are biaryl thio ethers really that oxidizable compared to other groups in SGX 523?

    • milkshake said

      considering that methylene exactly in that place was the site of hydroxylation in our compounds… (people in our metabolic group actually isolated few micrograms of that major metabolite from rats and succeeded in getting a reasonable 1H-NMR matching the initial MS/MS asignment)

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