ABSTRACT
The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.
Subject(s)
Drug Design , Heterocyclic Compounds, 3-Ring/pharmacology , Inhibitor of Apoptosis Proteins/metabolism , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitor of Apoptosis Proteins/chemical synthesis , Inhibitor of Apoptosis Proteins/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/toxicity , Aniline Compounds/chemical synthesis , Aniline Compounds/toxicity , Cardiovascular System/drug effects , Enzyme Inhibitors/toxicity , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/toxicity , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guinea Pigs , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Myocytes, Cardiac/drug effects , RatsABSTRACT
A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.
Subject(s)
Amines/chemical synthesis , Drug Design , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/chemistry , Mitochondrial Proteins/chemistry , Piperidines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Apoptosis Regulatory Proteins , Biomimetics , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.
Subject(s)
Amides/chemical synthesis , Aniline Compounds/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Amides/chemistry , Aniline Compounds/chemistry , Animals , Dogs , Heterocyclic Compounds, 2-Ring/chemistry , Mice , Molecular Structure , Protein Kinase Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.
Subject(s)
Chemistry, Pharmaceutical/methods , Neoplasms/drug therapy , Quinolines/chemistry , Quinolines/pharmacokinetics , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.
Subject(s)
Chemistry, Pharmaceutical/methods , Neoplasms/drug therapy , Quinolines/chemistry , Quinolines/pharmacokinetics , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Amines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Models, Chemical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Thiazoles/pharmacology , 3T3 Cells , Amides/chemistry , Amides/pharmacokinetics , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Female , Humans , Mice , Mice, Nude , Rats , Receptor, Macrophage Colony-Stimulating Factor/genetics , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.
Subject(s)
Alkynes/pharmacology , Antineoplastic Agents/pharmacology , Biomimetic Materials/pharmacology , Drug Discovery , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Oligopeptides/pharmacology , Alkynes/chemical synthesis , Alkynes/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dimerization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Inhibitor of Apoptosis Proteins/metabolism , Mice , Molecular Conformation , Neoplasms/pathology , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.
ABSTRACT
The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.