Optimization of a series of azabenzimidazoles identified from screening hit and the information gained from a co-crystal structure of the azabenzimidazole-based lead bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles and . These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 .
View Article and Find Full Text PDFWe report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound , a highly potent ATM inhibitor (ATM cell IC 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties.
View Article and Find Full Text PDFATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution).
View Article and Find Full Text PDFA novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo.
View Article and Find Full Text PDFThe first detailed studies of intramolecular aza-Prins and aza-silyl-Prins reactions, starting from acyclic materials, are reported. The methods allow rapid and flexible access toward an array of [6,5] and [6,6] aza-bicycles, which form the core skeletons of various alkaloids. On the basis of our findings on the aza-Prins and aza-silyl-Prins cyclizations, herein we present simple protocols for the intramolecular preparation of the azabicyclic cores of the indolizidines and quinolizidines using a one-pot cascade process of N-acyliminium ion formation followed by aza-Prins cyclization and either elimination or carbocation trapping.
View Article and Find Full Text PDFA method to prepare 1-substituted N-Boc-tetrahydro-β-carbolines was developed by lithiation followed by electrophilic substitution. The deprotonation to give the organolithium was optimized by in situ IR spectroscopy and showed that the Boc group rotates slowly at low temperature. The chemistry was applied to the synthesis of 9-methyleleagnine (N-methyltetrahydroharman) and 11-methylharmicine.
View Article and Find Full Text PDFEpidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation.
View Article and Find Full Text PDFThe chiral base n-BuLi/(-)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39-48% and ers up to 97 : 3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities.
View Article and Find Full Text PDFATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM.
View Article and Find Full Text PDFThe SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.
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