- 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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- Enzyme Inhibitors
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Compounds of formula (I), are aurora kinase inhibitors: wherein X is —N—, —CH2—N—, —CH2—CH—, or —CH—; R1 is a radical of formula (IA) wherein Z is —CH2—, —NH—, -0-, —S(O)— —S—, —S(O)2 or a divalent monocyclic carbocyclic or heterocyclic radical having 3-7 ring atoms; Alk is an optionally substituted divalent C1-C6 alkylene radical; A is hydrogen or an optionally substituted monocyclic carbocyclic or heterocyclic ring having 5-7 ring atoms; r, s and t are independently 0 or 1, provided that when A is hydrogen then at least one of r and s is 1; R2 is halogen, —CN, —CF3, —OCH3, or cyclopropyl; and R3 is a radical of formula (IB) wherein Q is hydrogen or an optionally substituted phenyl or monocyclic heterocyclic ring with 5 or 6 ring atoms; Z[!It!]1> is —S—, —S(O)—, —S(O)2—, —O—, —SO2NH—, —NHSO2—, NHC(═O)NH, —NH(C═S)NH—, Or —N(R4)—wherein R4 is hydrogen, C1-C3 alkyl, cycloalkyl, or benzyl; and Alk[!It!]1> and Alk[!It!]2> are, independently, optionally substituted divalent C1-C3 alkylene radicals; and m, n and p are independently 0 or 1. Data supplied from the esp@cenet datatbase—Worldwide d77
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Page/Page column 22
(2009/10/06)
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