ABSTRACT
OBJECTIVE: Stents have evolved through three generations, the latest of which are totally bioresorbable to include drugs targeting restenosis, the surface polymer eluting those drugs, and scaffolds on which those drugs are coated. These scaffolds, however, thus far, have been pharmacologically inactive and remain a potential site for delivering a second drug. Therefore, we sought to evaluate the possibility of modifying a bioresorbable polymer so that it can double as a scaffold for both a stent and a drug targeting impaired re-endothelialization and stent thrombosis. METHODS AND RESULTS: We successfully modified a standard bioresorbable terpolymer in a way found to be consistent with the covalent incorporation of lovastatin, as seen on NMR, into a backbone comprised of lactide, glycolide, ε-caprolactone, and lovastatin (60 : 15 : 10 : 15 parts by weight), respectively. This was accomplished through a reaction of the four components of the polymer at 100°C for 18 h in the presence of an alcohol initiator and a scandium catalyst. The resulting terpolymer was fabricated into a scaffold using a novel RSF system developed by 3D Biotek. CONCLUSION: It preliminarily appears feasible to fabricate a fourth-generation bioresorbable stent that has the potential to deliver two drugs to the site of the procedure-related vessel lumen injury.
Subject(s)
Absorbable Implants , Drug Carriers , Drug-Eluting Stents , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Lovastatin/administration & dosage , Polymers/chemical synthesis , Magnetic Resonance Spectroscopy , Materials Testing , Prosthesis DesignABSTRACT
The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
Subject(s)
Isoxazoles/chemical synthesis , Phenylurea Compounds/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Quinazolines/chemical synthesis , Administration, Oral , Animals , Binding, Competitive , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Drug Screening Assays, Antitumor , Female , Humans , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Macaca fascicularis , Male , Mice , Mice, Nude , Microsomes, Liver , Models, Molecular , Mutation , Neoplasm Transplantation , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Quinazolines/pharmacology , Urea/pharmacology , Animals , Dose-Response Relationship, Drug , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue Distribution , Urea/analogs & derivatives , Urea/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.
Subject(s)
Benzothiazoles/pharmacology , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Benzothiazoles/pharmacokinetics , Cell Line, Tumor , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Rats , Solubility , Substrate Specificity , Xenograft Model Antitumor AssaysABSTRACT
Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.
Subject(s)
Benzothiazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Benzenesulfonates/pharmacology , Benzothiazoles/pharmacokinetics , Bone Marrow/drug effects , Bone Marrow/pathology , Carbazoles/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Furans , Humans , Mice , Mice, Nude , Mice, SCID , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacokinetics , Phosphorylation/drug effects , Piperazines/pharmacology , Prognosis , Protein Interaction Mapping , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/pharmacology , Quinazolines/pharmacology , Sorafenib , Staurosporine/analogs & derivatives , Staurosporine/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.
Subject(s)
Antineoplastic Agents/chemistry , Urea/analogs & derivatives , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Mice, Nude , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacokinetics , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.
