- Imidazo[4,5-b]pyridine derivatives as inhibitors of aurora kinases: Lead optimization studies toward the identification of an orally bioavailable preclinical development candidate
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Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b] pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC50 = 0.015 ± 0.003 μM, Aurora-B IC50 = 0.025 μM, Aurora-C IC50 = 0.019 μM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.
- Bavetsias, Vassilios,Large, Jonathan M.,Sun, Chongbo,Bouloc, Nathalie,Kosmopoulou, Magda,Matteucci, Mizio,Wilsher, Nicola E.,Martins, Vanessa,Reynisson, Jóhannes,Atrash, Butrus,Faisal, Amir,Urban, Frederique,Valenti, Melanie,De Haven Brandon, Alexis,Box, Gary,Raynaud, Florence I.,Workman, Paul,Eccles, Suzanne A.,Bayliss, Richard,Blagg, Julian,Linardopoulos, Spiros,McDonald, Edward
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experimental part
p. 5213 - 5228
(2010/09/18)
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- Regioisomeric 3-, 4- and 5-aminomethyl isoxazoles: Synthesis and muscarinic activity
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A series of 3-, 4- and 5-aminomethyl isoxazoles and isoxazoles with one or two additional methyl groups at the heterocycle were synthesized in order to investigate the structural requirements, ie heterocyclic moiety, regiochemistry and length of an aminoalkyl unit, for muscarinic activity. This was assayed on isolated rabbit vas deferens (M1 receptor subtype) and isolated guinea-pig atrium (M2 receptor subtype) and ileum (M3 receptor subtype). The isoxazoles tested are one to three orders of magnitude less active than furane or oxadiazole derivatives, having similar structural characteristics except for the heterocycle. Thus, the differences in molecular point charges and charge distribution contribute to the muscarinic activity of these compounds more than small differences in molecular shape and conformational energies.
- Dannhardt,Kiefer,Lambrecht,Laufer,Mutschler,Schweiger,Striegel
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p. 839 - 850
(2007/10/03)
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