ABSTRACT
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Piperazines/therapeutic use , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Pyridines/therapeutic use , Pyrimidines/therapeutic use , Pyrimidinones/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Clinical Trials as Topic , Dogs , Drug Discovery , Humans , Isomerism , Madin Darby Canine Kidney Cells , Mice, Inbred BALB C , Mice, Nude , Mutation , Piperazines/chemistry , Piperazines/pharmacology , Proto-Oncogene Proteins p21(ras)/genetics , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15â¯nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aß40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aza Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
As part of an ongoing effort at Amgen to develop a disease-modifying therapy for Alzheimer's disease, we have previously used the aminooxazoline xanthene (AOX) scaffold to generate potent and orally efficacious BACE1 inhibitors. While AOX-BACE1 inhibitors demonstrated acceptable cardiovascular safety margins, a retinal pathological finding in rat toxicological studies demanded further investigation. It has been widely postulated that such retinal toxicity might be related to off-target inhibition of Cathepsin D (CatD), a closely related aspartyl protease. We report the development of AOX-BACE1 inhibitors with improved selectivity against CatD by following a structure- and property-based approach. Our efforts culminated in the discovery of a picolinamide-substituted 3-aza-AOX-BACE1 inhibitor absent of retinal effects in an early screening rat toxicology study.
ABSTRACT
The ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aß levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.
