ABSTRACT
With renewed interest in atropisomerism of drug molecules, efficient methods to experimentally determine torsion rotational energy barriers are needed. Here, we describe use of the chiral phosphoric acid solvating agent (+)-TiPSY to resolve the signals of atropisomers in 19F NMR and to use the data to study the kinetics of racemization and determine the rotational energy barrier of clinical compound MRTX1719. This method is complimentary to traditional chiral high-performance liquid chromatography (HPLC) and enhances the toolkit for chiral analysis techniques.
ABSTRACT
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.
Subject(s)
Antineoplastic Agents/therapeutic use , Indoles/therapeutic use , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Crystallography, X-Ray , Dogs , Humans , Indoles/chemical synthesis , Indoles/metabolism , Indoles/pharmacokinetics , Male , Mice, Inbred BALB C , Mitogen-Activated Protein Kinase 1/chemistry , Mitogen-Activated Protein Kinase 1/metabolism , Molecular Structure , Phosphorylation/drug effects , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Mas , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.
Subject(s)
Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Propionates/metabolism , Protein Binding/drug effects , Binding Sites , Cell Line , Humans , Kelch-Like ECH-Associated Protein 1/chemistry , Molecular Conformation , NF-E2-Related Factor 2/chemistry , Propionates/chemical synthesis , Propionates/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.
Subject(s)
Drug Discovery , Isoquinolines/chemical synthesis , Drug Design , Isoquinolines/chemistry , Molecular StructureABSTRACT
A highly selective method to protect the 11 beta-OH position of steroid (1) has been developed. This is achieved via double silyl protection of the 11 beta, 17 alpha-diol, followed by selective desilylation of the 17 alpha-OH under basic conditions without the need for a fluoride source.
Subject(s)
Steroids/chemistry , Steroids/chemical synthesis , Structure-Activity RelationshipABSTRACT
The neutral endopeptidase inhibitor (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid 2 is metabolized to acyl glucuronide 3. Unprecedentedly, at pH 7.4, 3 does not undergo the O-acyl migration characteristic of acyl glucuronides but rapid, eliminative cyclization (t1/2 at 37 degrees C, 10.2 min) to glutarimide 4. Glucuronide 3 was synthesized efficiently via acylation of benzylglucuronate with N-benzyloxymethyl-protected 2. Glucuronide and imide reacted rapidly in aqueous solution, pH 7.4, with amino acids and glutathione to form stable amides and unstable thioesters. Imide 4 acylated eight lysine Nepsilon-amino groups of human serum albumin. Rapid cyclization of 3 was attributed to attack on the ester linkage by an unusually nucleophilic glutaramide NH (pKa in 2 = 9.76). N-propyl 3 was refractory to acyl migration and cyclization. This suggested a synthetic strategy for preparing analogues of 2 that form chemically stable acyl glucuronides.
Subject(s)
Glucuronides/chemistry , Neprilysin/antagonists & inhibitors , Neprilysin/chemistry , Pentanoic Acids/chemistry , Pentanoic Acids/metabolism , Piperidones/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/chemical synthesis , Thiadiazoles/metabolism , Animals , Cyclization , Humans , Hydrogen-Ion Concentration , Hydrolysis , Male , Piperidones/chemistry , Piperidones/pharmacokinetics , Rats , Rats, Wistar , Serum Albumin/chemistry , Stereoisomerism , Thiadiazoles/pharmacokineticsABSTRACT
The nuclear magnetic shieldings of two chloropyrimidine species have been predicted and analyzed by means of ab initio and DFT methods. The results have been compared with the experimental values and with those from other database-related approaches. These dataset-based techniques are found to be particularly valuable because of the accurate and instantaneous prediction of the 13C chemical shifts. On the other hand, only a few quantum chemistry based approaches were showed to be the most precise to predict 1H chemical shifts and to elucidate unequivocally the 1H NMR spectra of the regioisomeric mixture under study. Special emphasis was put on incorporating the solvent effect, implicitly, or explicitly. The influence of the level of theory and basis set in the predicted values has also been discussed.
Subject(s)
Chlorine/chemistry , Pyrimidinones/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Time FactorsABSTRACT
Simply reversing the order of addition of aqueous acid and Et2 O to the Barbier intermediate 1 of the known indium-mediated allylation leads to unprecedented deoxygenative rearrangements [Eq. (a)].
