Two deals involving companies in the fragment space were announced today. I don’t have inside information on either of these, but superficially they are strikingly different.
In the first, Australia’s Biota has agreed to acquire UK-based Prolysis Limited, which previously published some nice work on using FBLD to discover new antibiotic leads (see here and here). The price? Just $10.8 million. However, Biota did say it plans to invest up to $25 million over the next three years on programs Prolysis started.
At the same time, UK-based Astex Therapeutics announced a new partnership with GlaxoSmithKline. The deal is for multiple targets in multiple therapeutic areas, with Astex focused on fragment screening and lead discovery and GSK focused on optimization of the resulting leads as well as preclinical and clinical development. The price? $33 million in up-front cash and equity, with a total potential of more than $500 million (BioBucks).
Astex of course is one of the few intact survivors of the first wave of fragment-based companies and has put several compounds into the clinic, including AT9283, AT7519, and others. It’s encouraging to see that deals of this size are still being done for what look to be fairly early stage collaborations.
Showing posts with label Prolysis. Show all posts
Showing posts with label Prolysis. Show all posts
12 November 2009
08 January 2009
Ligand efficiency for antibiotics
Back in October of last year we highlighted a paper in Science that disclosed a new antibiotic targeting the bacterial protein FtsZ. The compound was derived through fragment-based techniques, though at the time no details were provided. A new paper in BMCL now provides some of the early medicinal chemistry, and also introduces an interesting new tool for evaluating antibiotics.
As mentioned in the Science paper, the researchers (led by Prolysis but with a number of contributors from Evotec and Key Organics) started with the fragment-like (MW = 151, 11 heavy atoms) 3-methoxybenzamide. An initial survey of “SAR by catalog” soon moved to the synthesis of analogs that could be assembled in up to four steps from commercially available compounds. This study found that the amide was essential, and only limited substitutions around the aromatic ring were tolerated. Turning to the alkoxy group, the authors took the classic “methyl, ethyl, butyl” approach, but kept going all the way to dodecyl. Intriguingly, a nonyloxy substituent proved to be optimal, better than either 8 or 10 carbon chains. Adding two fluorine atoms to the aromatic ring improved the potency further. Although the paper does not describe the final push to PC190723, the authors do describe the desire to replace the long alkyl chain and its likely attendant problems.
The paper also defines an interesting variation of ligand efficiency:
Antibacterial efficiency = -ln (MIC) / N, where
MIC = minimum inhibitory concentration (mg/ml) and
N = non-hydrogen atoms
Although the metric has a few quirks (for example, low-efficiency compounds can actually have negative numbers), “good” values correspond roughly to good LE values; clinically approved low molecular weight antibiotics have antibacterial efficiencies in the 0.26-0.32 mg/ml/atom range.
So for all you folks working on antibiotics, not only are fragments a viable starting point, you now have a new way to evaluate progress.
As mentioned in the Science paper, the researchers (led by Prolysis but with a number of contributors from Evotec and Key Organics) started with the fragment-like (MW = 151, 11 heavy atoms) 3-methoxybenzamide. An initial survey of “SAR by catalog” soon moved to the synthesis of analogs that could be assembled in up to four steps from commercially available compounds. This study found that the amide was essential, and only limited substitutions around the aromatic ring were tolerated. Turning to the alkoxy group, the authors took the classic “methyl, ethyl, butyl” approach, but kept going all the way to dodecyl. Intriguingly, a nonyloxy substituent proved to be optimal, better than either 8 or 10 carbon chains. Adding two fluorine atoms to the aromatic ring improved the potency further. Although the paper does not describe the final push to PC190723, the authors do describe the desire to replace the long alkyl chain and its likely attendant problems.
The paper also defines an interesting variation of ligand efficiency:
Antibacterial efficiency = -ln (MIC) / N, where
MIC = minimum inhibitory concentration (mg/ml) and
N = non-hydrogen atoms
Although the metric has a few quirks (for example, low-efficiency compounds can actually have negative numbers), “good” values correspond roughly to good LE values; clinically approved low molecular weight antibiotics have antibacterial efficiencies in the 0.26-0.32 mg/ml/atom range.
So for all you folks working on antibiotics, not only are fragments a viable starting point, you now have a new way to evaluate progress.
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