Oxi4503
CA4 and CA1 (Oxi4503) only differ with a supplementary OH group on the second ring.
All combretastatin, originally derived from the African willow tree Combretum caffrum by Pettit are structurally related to Colchicine, substance studied in the 30s and 40s as an antitumor agent, but its toxicity precluded further clinical development.
Combretastatins consist in 2 phenyl rings tilted at 50-60° to each other and linked by 2 carbon bridge with several methoxy substitutions on the ring system. In most studies and patents , the 3 trimethoxyphenyl groups at 3, 4, 5 position on ring A (H3C0), which is also found on the Colchicine is considered as an essential part of the pharmaceutical activity and kept constant.
CA4 and CA1 are not water soluble so the Phosphate prodrugs has been developped. The single OH group of CA4 has been replaced by a phosphate cleavage OPO3 to form CA4P and the two OH group of CA1 has been replaced by 2 phosphate cleavages to form CA1P which is a diphosphate.
As far as now, recent data (Holwell et al, 2001) suggest that CA1P may be more effective tha CA4P in vivo (slightly more toxic, but dose reduced by a factor of 2)with a better therapeutic window. The reason is not explained so far, but it may be linked to the different phsphate cleavage (that I suppose change the pharmacokinetic profile).
It has been also said (Holwell et al, 2002) that the mechanism of action appears to be similar to CA4P, which finding correlate what I have just explained concerning the structure.
Personnaly, based on my reading, I don't expect wondrous things coming from that compound except a wider therapeutic window than the actual CA4P which is quite narrow (but sufficient) if you go through the ASCO abstract from 2000 to 2002.
It will certainly allow higher doses or more frequent doses which will trend to a higher tumor shrinkage.
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