WO2006113837

Hi Again SKB, Nice AKT inhibitors.

This benzimidazole core keeps popping up in the patent literature… Maybe there’s something to it. I see you guys vary the heck out of the alkoxy-amino region. Some nice intermediates worth perusing there.

As for the binding motif, well, AKT appears to be difficult to crystallize, or else why would folks be looking at PKA mutants as PKB models? (1XH4, 1XH5, 1XH6, 1XH7, 1XH8, 1XH9, and 1XHA) KP is not aware of any PDBs with the core, and the two APO’s of akt are teh suq, but my feeling is that 2F7Z has some clues.

Yah, Yah I know the overlay is ‘backwards’ compared to the 2D models… Use your rimagination. This seems reasonable though and puts the oxadiazole at the hinge, the alkyne pointed towards H1, and the primary amine in the phosphate binding region. NC1=NON=C1C2=NC3=C(C#CC(C)(O)C)N=C(O[C@H]([C@H](COC)N)C4=CC=CC=C4)C=C3N2CC

Details…

Couple things…

• Looks like Org Syn volume 84 is starting to roll out on the web.
• Pipeline looks to be down today 😦
• Some Canadian company, bought some company in Tucson that has some kinase inhibitors (Pi3K, and AKT) ‘in late preclinical development’. For those of us following along at home, that’s code for having compounds with A) crummy PK B) poor selectivity C) CYP issues – or more likely – all of the above. Only reason I can see to list all the programs in the press release is that they are now for sale. Any bets on what they do with the American side of the company?
• Array announced its p38 program is ready for prime-time. (Of note Array has some of their patents applications downloadable) From that list it looks like plenty of MEK and AKT inhibitors… but P38? Yah there’s a couple from ’04.

US20060241149

To Kinasepro, the real personality behind Sorafenib, is the part about how they optimized against RAF only to find out later that it was the VEGFR2 and PDGFR-b activity that was driving the efficacy. Hmm, somehow they don’t quite put it that way in the Nature Reviews DD article… Bayer has a couple PDB’s deposited for Sorafenib / BAY439006 / Nexavar (RAF; 1UWH, 1UWJ), but if you want a Urea bound to VEGF all you’ve got is 1YWN. Does this mean GSK > SKB? I tend to think US20060241149 will put an answer to that.

Yah yah 1YWN was a GSK Japan offering, while the current application is a King of Prussia SKB claim but what’s this new application all about? Mmmmm, I think you’re going to have to do better then a little TIE2 activity to make me a believer.

So I here you thinking, ‘aww, c’mon the Piperazines are cool!’ Bleh, been there done that – and the fused 5? Yah, yah I guess but hasn’t somebody already been there? I hope this is one of those applications dropped just to prevent someone else from going there… Oh, but if you’ve been wondering why you keep seeing these pyridines bearing a 2-methyl carboxamide it’s because if the pyridyl binds the hinge, you get a modest bump in activity, and:

O=C(NC3=CC=C(CN4CCN(C)CC4)C(C(F)(F)F)=C3)N(CC5)C(C5=C2)=CC=C2OC1=CC=NC(C(NC)=O)=C1 O=C(NC3=CC=C(Cl)C(C(F)(F)F)=C3)NC(C=C2)=CC=C2OC1=CC=NC(C(NC)=O)=C1

DE102005020104

and DE102005020105. Guten Tag Schering AG,

Further along the road with the thiazolidinones, eh?  I like the title: New thiazolidinone without basic nitrogen, their production and use as drugs

Kinasepro is always happy to see more Plk1 inhibitors, but hey I’ll admit that I haven’t a clue whats going on with these – and now consider an earlier post on your analogous series, ummm, wrong. The only PDBs that give KP a hint as to what could be going on here are from some compounds bound to PI3K: 2A4Z, and 2A5U. O=C(N(CC)/C(S2)=C(C(NCC(F)(F)F)=O)\C#N)/C2=C/C1=C(C)N=CN1 O=C(N(CC)/C(S2)=C(C(NCC#C)=O)\C#N)/C2=C/C1=CC=C(N3CCCC3)C=C1

US20060241297

Hi again Cyclacel, Good idea to cover the pyridines too. Thanks for giving us the data. And hey, it appears you can walk around the activity wheel a little by varying the amine portion of the aminothiazole, but less then 10-fold over all the CDKs and GSK3 / Aurora? Unless your not showing us your ace, it makes Kinasepro wonder just how selective your PLK1 inhibitors are.

CC(N=C(NCCOC)S3)=C3C1=NC(NC2=CN=C(OC)C=C2)=NC=C1

A little lite weekend reading

Hello KinaseFans, Kinasepro may very well not get to all of these, but here’s the list for this week:

US20060241301 < < TIE2
US20060241297
US20060241179 < SKB < P38
US20060241151 < Amgen < CDK
US20060241149 < SKB < VEGF
US20060241145
US20060241131 < Pfizer < JAK3
US20060241127 < Bayer < Rho
US20060241115 < Amgen < Spectrum
US20060241112
US20060241106 < < HSP90
US20060241104 < BMS < c-Met

US7125875

The claims are basically: Swallow Dasatinib wherein the cancer is Gleevec resistant. Read the J Med Chems (here, and here). BMS has been prolific in writing about their aminothiazoles and there’s plenty of bioorg med chem lett’s too. For anyone who’s been living under a rock for the last couple years, Dasatinib is BMS’s SRC / ABL compound. They use the (cough*stupid*cough) term ‘pan-SRC selective’ since it hits: YES / LCK / LYN / FYN / etc.

…and thats just the profile they want to tell us about…

PDB = 2GQG

O=C(C2=CN=C(NC3=NC(C)=NC(N4CCN(CCO)CC4)=C3)S2)NC1=C(C)C=CC=C1Cl BMS35482513 Dasatinib

US7125888

Hi Merck, VEGFR2 Inhibitors?!

**yawns**

If my read is correct these sound like ‘pure’ VEGF compounds though. Ok thats interesting enough I guess, ocular indications, macular degeneration, yada-yada-yada. The patent claims the compounds in combination NSAIDs.

O=C1C=C(C4=CC3=NC=C(C5=CC=CC=C5)N3C=C4)C=CN1CCCN2CCCCC2

US20060235065

Wie Gehts Roche Penzeburg?

This doesn’t otherwise strike Kinasepro as a very crowded chemical space, but it looks as though Roche is stepping a little close to Astex toes on this one… Looks as though Astex borrowed the general idea from Aventis, so hey thats just the way it goes I guess.

There’s a handful of PDB’s such as the 2C3K and 2C3L (CHK1) that suggest how these compounds bind to kinases.

US20060235025

How now Schering-Plough, Nice purvalanol analogs as CDK2 inhibitors.

Anything earthshaking here? Hmm… Not really, but look hard enough, and KP always learns something.

Yep, hadn’t noticed the bromide as an isopropyl isostere before, but this is a continuation from US2006041131, WO2004022559. Schering has been beating on this and other 6-5 purine isosteres for some time (WO2004026877). There’s been plenty of Biotech sniffing around here. Vernalis has a similar CDK series (WO2004087707), and a Bioorg. Med. Chem. Lett. 2005, 863 (appears they’ve dropped the series).  Ono has some c-Jun (WO2005035516) inhibitors on the scafford. So whats new here? Vernalis describes selectivity issues.  Maybe they cracked that nut, otherwise its not obvious to me.
BrC2=C1N(N=C2)C(NC3=CC=NC=C3)=CC(C4CCCNC4)=N1 BrC2=C1N(N=C2)C(NC3=CC=CN=C3)=CC(N4CCC[C@@H]4CO)=N1 CC(C)N2C=NC1=C(NC3=CC(Cl)=CC=C3)N=C(N[C@H]([C@H](C)C)CO)N=C12