DAST (BAY 73-4506)

It’s Bayer’s Ph2 follow-on to Sorafenib.  VEGF / RAF yadda yadda… Don’t have the structure, but maybe it’s one of these:

from polymorph apps:

WO/2008/058644 –            WO/2008/079968
WO/2008/043446 –            WO/2008/079972

& yeh, that is Fluoro-Nexavar…

Masitinib

aka: Masivet, Kinavet & AB-1010 quietly joined the Phase iii club when it went Ph3 back in December.

WO/2008/98949

Re-Engineering Gleevec

Alex Fernandez thinks he has a dehydron in action with Gleevec & c-Kit:

The interest of this goes way beyond this particular drug and this particular side effect. The idea is we could demonstrate for the first time that you can take a drug with side effects and re-engineer it to curb those side effects, Fernandez said in a telephone interview. (Reuters)

Adding a methyl group alpha to the the pyridine will make the activity of most kinases go away given a steric clash with the neighboring carbonyl. It’s interesting that the c-Kit activity stays behind, but the evidence given for the dehydron effect is through molecular dynamics and while as a rule I’ll try not to hold that against them, I don’t believe that the authors give a satisfactory answer as to why this new methyl group does not negate the compounds c-Kit activity through a simple steric interaction.

J Clin Invest 2007, 117, 4044
related: Cancer Res. 2007, 67 (9): 4028-33

Nippon Shanyaku took the alternate tack of making the core pharmacophore more potent and made it hit other things… In the discovery of the ph1 compound NS-187 (Inno-406):

Read all about it in the ’06 BMCL, the ’07 BMCL, the 2E2B, or through an Open Access offering here.

Tasigna

aka nilotinib, AMN-107 is a Novartis’ follow-on to Gleevec.

wiki; clinic; WO/2002/022597

Motesanib

Motesanib diphosphate, AMG-706 hits: Vegfr1,2,3, c-kit, Pdgfr-b, and Ret

Salt: bisphosphonate
Clinic Ph iii: NSCLC
Cancer Res.; WO/2002/066470

E7080

US20070117842 is a polymorph application, and there’s been a fair amount of IP activity around the compound. Indications are its E7080: an oral PhI Vegf, FGF, Pdgf, C-Kit, etc compound which first touched down in WO/2004/080462.

Axitinib

aka AG-013736 is Pfizer’s Vegf / PDGF / cKit inhibitor.

’06 Asco, clinic: ph 2; process app; pct

Plexxikon’s cFms/cKit stuff:

Some of Plexxicon’s latest cKit / cFms stuff has published, and surprise-surprise its got their ‘scaffold’. The choice of where to tag on amines suggests the following motif:

This week: US20070032519
Last week: WO/2007/013896
Last year: WO/2006/009797

US20060281764

WTF J&J, Oxime-aldehydes? FLT3, TRKb, cKit inhibitors… Shinogi has some related EGF compounds: WO2006106721, and there’s a Biorg Med Chem Lett with the motif in CDK so its not unheard of. Quinazoline isosteres… Cool.

Update >> There’s a couple other relatives that make this a family of applications which all published last Thursday:

 

This looks like the primary series, and the aniline appears to dial in TRKB – albeit not all that dramatically: US20060281772

US20060281768

 

Hmm… is LG293 TRKb?