ABSTRACT
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Subject(s)
Down-Regulation/drug effects , Drug Discovery , Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Small Molecule Libraries/pharmacology , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Molecular Structure , Prostatic Neoplasms/pathology , Pyridazines/chemical synthesis , Pyridazines/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.
Subject(s)
Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Humans , Ligands , Male , Models, Molecular , Molecular Structure , Molecular Weight , Prostatic Neoplasms/metabolism , Pyridazines/chemical synthesis , Pyridazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Antineoplastic Agents/chemistry , Aspartic Acid/chemistry , Aspartic Acid/genetics , Binding Sites , Combinatorial Chemistry Techniques , Cyclin-Dependent Kinase 2/metabolism , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Mice , Mice, Nude , Molecular Structure , Piperazines/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Indazoles/pharmacology , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Epidermal Growth Factor/pharmacology , Ether-A-Go-Go Potassium Channels , Female , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Indazoles/chemical synthesis , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Lapatinib , Male , Metabolic Clearance Rate , Mice , Mice, Nude , Mice, SCID , Microsomes/drug effects , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Rats , Rats, Wistar , Survival Rate , Xenograft Model Antitumor AssaysABSTRACT
Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.
