- Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues
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The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering log D was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogues thus provide a credible additional route to further development of the series.
- Large, Jonathan M.,Osborne, Simon A.,Smiljanic-Hurley, Ela,Ansell, Keith H.,Jones, Hayley M.,Taylor, Debra L.,Clough, Barbara,Green, Judith L.,Holder, Anthony A.
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p. 6019 - 6024
(2013/10/22)
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- HETEROCYCLIC COMPOUNDS AND USE THEREOF AS ERK INHIBITORS
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Disclosed are the ERK inhibitors of formula 1.0: [Formula (1.0)] and the pharmaceutically acceptable salts, esters and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
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Page/Page column 252
(2009/01/23)
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- POLYCYCLIC INDAZOLE DERIVATIVES AND THEIR USE AS ERK INHIBITORS FOR THE TREATMENT OF CANCER
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Disclosed are the ERK inhibitors of formula 1.0: (Chemical formula should be inserted here as it appears on abstract in paper form) and the pharmaceutically acceptable salts, esters and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
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Page/Page column 262
(2009/01/24)
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- Apparent allyl rotation and Pd-N bond rupture in allylpalladium complexes with N-donor ligands - Evidence of an associative mechanism
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The new didentate N-donor ligands 2-(4-methyl-1H-pyrazol-1-yl)pyrimidine (4Me-pzpm, 1) and 2-(4-bromo-1H-pyrazol-1-yl)pyrimidine (4Br-pzpm, 2) have been synthesised and used to obtain the allylpalladium derivatives [Pd(η3-2Me-C3H4)(NN′)]X [X = BAr′4-, NN′ = 1 (3), NN′ = 2 (4); X = CF3SO3-, NN′ = 1 (5), NN′ = 2 (6)]. In complexes 3-6 two types of fluxional process have been found: apparent allyl rotation that is observed as Hsyn-Hsyn, H anti-Hanti interconversions and H4-H 6 interchange of the pyrimidine protons that must involve Pd-N(pm) bond rupture. The influence of different factors on both processes - such as the nature of the N-donor ligand, counterion, solvent, complex concentration and addition of water - has been studied. It has been concluded that the apparent allyl rotation has a lower free energy of activation and in both cases the presence of a species with coordinating ability favours the process. Negative entropies of activation have been found. Associative mechanisms involving participation of five-coordinate intermediates have been proposed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Jalon, Felix A.,Manzano, Blanca R.,Moreno-Lara, Belen
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p. 100 - 109
(2007/10/03)
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