This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Structure−activity relationships in a series of 4-1H-indazol-5-ylaminopyrrolo2,1-f1,2,4triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with ...excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
The identification of a potent series of IKK-β selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (
22j) in the LPS-induced TNF-α release mouse ...model are described.
The identification of a potent series of IKK-β selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (
22j) in the LPS-induced TNF-α release mouse model are described.
Analogs utilizing proline isosteres in IGF-1R/IR inhibitors are disclosed. X-ray co-crystallography of selected analogs reveals information key to target potency.
Pyrrolidine, pyrrolidinone, ...carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo2,1-
f1,2,4triazine nucleus is described. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 ...carbamates with potent biochemical and cellular activities.
A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo2,1-
f1,2,4triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.
Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C−C, ...C−O, C−N, C−S, and C−P bond formation.
2-Aryl-2,2-difluoroacetamido-proline and pipecolate esters are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray ...structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 phenyl ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.
Novel C-5 aminomethyl pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human ...tumor xenograft models. It is hypothesized that its C-5 homopiperazine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine,
1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose–phosphate portion of the ATP binding pocket.
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human ...tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
The evolution of
2, a C-4-methylcarbonate analogue of paclitaxel with minimal oral bioavailability and oral efficacy, into its C-3′-
t-butyl-3′-
N-
t-butyloxycarbonyl analogue (
15i), a novel taxane ...with oral efficacy in preclinical models that is comparable to iv administered paclitaxel, is described.
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