RÉSUMÉ
In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.
Sujet(s)
Interleukin-1 Receptor-Associated Kinases/antagonistes et inhibiteurs , Lymphome B diffus à grandes cellules/traitement médicamenteux , Thérapie moléculaire ciblée , Facteur de différenciation myéloïde-88/génétique , Quinazolines/composition chimique , Quinazolines/pharmacologie , Administration par voie orale , Animaux , Lignée cellulaire tumorale , Conception de médicament , Femelle , Humains , Interleukin-1 Receptor-Associated Kinases/composition chimique , Lymphome B diffus à grandes cellules/génétique , Lymphome B diffus à grandes cellules/anatomopathologie , Souris , Modèles moléculaires , Mutation , Conformation des protéines , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacocinétique , Inhibiteurs de protéines kinases/pharmacologie , Quinazolines/administration et posologie , Quinazolines/pharmacocinétique , Rats , Rat Wistar , Relation structure-activité , Distribution tissulaire , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Tumeurs du sein/traitement médicamenteux , Antagonistes des récepteurs des oestrogènes/usage thérapeutique , Composés hétérocycliques 3 noyaux/usage thérapeutique , Indazoles/usage thérapeutique , Animaux , Antinéoplasiques/synthèse chimique , Antinéoplasiques/pharmacocinétique , Chiens , Tests de criblage d'agents antitumoraux , Antagonistes des récepteurs des oestrogènes/synthèse chimique , Antagonistes des récepteurs des oestrogènes/pharmacocinétique , Récepteur alpha des oestrogènes/métabolisme , Composés hétérocycliques 3 noyaux/synthèse chimique , Composés hétérocycliques 3 noyaux/pharmacocinétique , Humains , Indazoles/synthèse chimique , Indazoles/pharmacocinétique , Cellules MCF-7 , Mâle , Souris SCID , Microsomes du foie/métabolisme , Structure moléculaire , Rats , Relation structure-activité , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.
Sujet(s)
Interleukin-1 Receptor-Associated Kinases/antagonistes et inhibiteurs , Pyrroles/composition chimique , Thiazines/composition chimique , Animaux , Sites de fixation , Cellules Caco-2 , Chiens , Conception de médicament , Période , Hépatocytes/cytologie , Hépatocytes/métabolisme , Humains , Interleukin-1 Receptor-Associated Kinases/métabolisme , Lymphome B diffus à grandes cellules/métabolisme , Lymphome B diffus à grandes cellules/anatomopathologie , Simulation de dynamique moléculaire , Mutation , Facteur de différenciation myéloïde-88/génétique , Facteur de différenciation myéloïde-88/métabolisme , Perméabilité/effets des médicaments et des substances chimiques , Protein kinases/composition chimique , Protein kinases/métabolisme , Pyrroles/pharmacocinétique , Pyrroles/pharmacologie , Rats , Relation structure-activité , Thiazines/pharmacocinétique , Thiazines/pharmacologieRÉSUMÉ
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
Sujet(s)
Antinéoplasiques/pharmacologie , Interleukin-1 Receptor-Associated Kinases/antagonistes et inhibiteurs , Lymphome B diffus à grandes cellules/traitement médicamenteux , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Administration par voie orale , Animaux , Antinéoplasiques/administration et posologie , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacocinétique , Lignée cellulaire tumorale , Cristallographie aux rayons X , Chiens , Femelle , Humains , Interleukin-1 Receptor-Associated Kinases/composition chimique , Lymphome B diffus à grandes cellules/génétique , Spectroscopie par résonance magnétique , Mâle , Souris SCID , Mutation , Facteur de différenciation myéloïde-88/génétique , Inhibiteurs de protéines kinases/administration et posologie , Pyrimidines/composition chimique , Pyrroles/composition chimique , Rat Wistar , Relation structure-activité , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.
RÉSUMÉ
A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
Sujet(s)
Récepteur alpha des oestrogènes/métabolisme , Ombelliférones/composition chimique , Ombelliférones/pharmacologie , Administration par voie orale , Animaux , Lignée cellulaire tumorale , Coumarines/composition chimique , Coumarines/pharmacocinétique , Coumarines/pharmacologie , Régulation négative/effets des médicaments et des substances chimiques , Récepteur alpha des oestrogènes/analyse , Humains , Simulation de docking moléculaire , Rats , Ombelliférones/pharmacocinétiqueRÉSUMÉ
4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles.
Sujet(s)
Hydrocarbures halogénés/composition chimique , Magnésium/composition chimique , Nitriles/synthèse chimique , Pyrazoles/synthèse chimique , Techniques de chimie combinatoire , Structure moléculaire , Nitriles/composition chimique , Composés organométalliques/composition chimique , Pyrazoles/composition chimique , StéréoisomérieRÉSUMÉ
The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.
Sujet(s)
Pyrazoles/composition chimique , Pyrimidines/composition chimique , Récepteur FGFR1/antagonistes et inhibiteurs , Animaux , Sites de fixation , Cristallographie aux rayons X , Dimérisation , Conception de médicament , Humains , Ligands , Souris , Souris knockout , Modèles moléculaires , Structure moléculaire , Phosphorylation , Pyrazoles/synthèse chimique , Pyrazoles/pharmacologie , Pyrimidines/synthèse chimique , Pyrimidines/pharmacologie , Récepteur FGFR1/composition chimique , Récepteur FGFR1/métabolisme , Relation structure-activitéRÉSUMÉ
Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.
Sujet(s)
Composés hétérocycliques 3 noyaux/synthèse chimique , Composés hétérocycliques avec 4 noyaux ou plus/synthèse chimique , Protéines proto-oncogènes c-akt/antagonistes et inhibiteurs , Régulation allostérique , Animaux , Biodisponibilité , Marqueurs biologiques/métabolisme , Lignée cellulaire tumorale , Tests de criblage d'agents antitumoraux , Composés hétérocycliques 3 noyaux/composition chimique , Composés hétérocycliques 3 noyaux/pharmacologie , Composés hétérocycliques avec 4 noyaux ou plus/composition chimique , Composés hétérocycliques avec 4 noyaux ou plus/pharmacologie , Humains , Imidazoles/synthèse chimique , Imidazoles/composition chimique , Imidazoles/pharmacologie , Souris , Souris nude , Modèles moléculaires , Transplantation tumorale , Protéines proto-oncogènes c-akt/métabolisme , Pyrazines/synthèse chimique , Pyrazines/composition chimique , Pyrazines/pharmacologie , Pyrazoles/synthèse chimique , Pyrazoles/composition chimique , Pyrazoles/pharmacologie , Pyridazines/synthèse chimique , Pyridazines/composition chimique , Pyridazines/pharmacologie , Pyridines/synthèse chimique , Pyridines/composition chimique , Pyridines/pharmacologie , Quinazolines/synthèse chimique , Quinazolines/composition chimique , Quinazolines/pharmacologie , Rats , Relation structure-activité , Transplantation hétérologueRÉSUMÉ
Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.
Sujet(s)
Amides/composition chimique , Modèles chimiques , Alkylation , Cristallographie aux rayons X , Éphédrine/composition chimique , Hydroxylation , Cinétique , Spectroscopie par résonance magnétique , Conformation moléculaire , Oxazoles/composition chimique , Proline/composition chimique , Stéréoisomérie , Soufre/composition chimique , ThermodynamiqueRÉSUMÉ
An asymmetric synthesis of aza analogues of the ABC ring system of phorbol and related compounds containing the 5-7-6-fused framework of daphnane involved construction of the central seven-membered ring by a regioselective reduction of a chiral imide and cyclization with trifluoromethanesulfonic acid. Subsequent demethylation and oxidative dearomatization of ring C afforded an enantiopure dienone 20 with the same relative and absolute configuration at the 9- and 10-positions of the phorbol skeleton.
Sujet(s)
Composés aza/synthèse chimique , Diterpènes , Phorbols/synthèse chimique , Terpènes/synthèse chimique , Catalyse , Chimie organique/méthodes , Cristallographie aux rayons X , Cyclisation , Spectroscopie par résonance magnétique , Structure moléculaire , Oxydoréduction , StéréoisomérieRÉSUMÉ
The degree to which the rotations about the C-N and Ar-CO bonds of aromatic amides occur in a concerted manner was investigated by a variety of NMR and kinetic techniques. Otherwise complex kinetic analyses were simplified by exploiting symmetry and asymmetry in the N-substituents of amides. In 2-unsubstituted 1-naphthamides bearing branched N-substituents, most conformational changes about the amide group were by correlated rotation, though uncorrelated Ar-CO rotation also occurred to some extent. In 2-substituted 1-naphthamides, correlated rotation accounted for all of the Ar-CO rotations, though a significant amount of uncorrelated C-N rotation also occurred. Naphthamides bearing branched N-substituents thus turn out to be efficient molecular gears: Compound 12 showed almost no gear slippage.