ABSTRACT
ADCs based on the natural product maytansine have been successfully employed clinically. In a previous report, ADCs based on hydrophilic non-cell permeable maytansinoids was presented. The authors in this report further explore the maytansine scaffold to develop tubulin inhibitors capable of cell permeation. The research resulted in amino-benzoyl-maytansinoid payloads that were further elaborated with linkers for conjugating to antibodies. This approach was applied to MUC16 tumor targeting antibodies for ovarian cancers. A positive control ADC was evaluated alongside the amino-benzoyl-maytansinoid ADC and the efficacy observed was equivalent while the isotype control ADCs had no effect.
Subject(s)
Immunoconjugates/metabolism , Maytansine/chemistry , Tubulin Modulators/chemistry , Animals , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Maytansine/metabolism , Mice, SCID , Neoplasms/drug therapy , Neoplasms/pathology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/metabolismABSTRACT
Natural products have been used for many medicinal purposes for centuries. Antibody drug conjugates (ADCs) have utilized this rich source of small molecule therapeutics to produce several clinically useful treatments. ADCs based on the natural product maytansine have been successful clinically. The authors further the utility of the anti-cancer natural product maytansine by developing efficacious payloads and linker-payloads for conjugating to antibodies. The success of our approach was realized in the EGFRvIII targeting ADC EGFRvIII-16. The ADC was able to regress tumors in 2 tumor models (U251/EGFRvIII and MMT/EGFRvIII). When compared to a positive control ADC, the efficacy observed was similar or improved while the isotype control ADCs had no effect.
Subject(s)
Antineoplastic Agents/pharmacology , Immunotoxins/pharmacology , Maytansine/pharmacology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/immunology , CHO Cells , Cell Line, Tumor , Cricetulus , ErbB Receptors/immunology , Female , Humans , Hydrophobic and Hydrophilic Interactions , Immunotoxins/chemistry , Immunotoxins/immunology , Kinetics , Male , Maytansine/chemical synthesis , Maytansine/chemistry , Mice , Xenograft Model Antitumor AssaysABSTRACT
The inflammatory response associated with the activation of C-C chemokine receptor CCR2 via it's interaction with the monocyte chemoattractant protein-1 (MCP-1, CCL2) has been implicated in many disease states, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, asthma and neuropathic pain. Small molecule antagonists of CCR2 have been efficacious in animal models of inflammatory disease, and have been advanced into clinical development. The necessity to attenuate hERG binding appears to be a common theme for many of the CCR2 antagonist scaffolds appearing in the literature, presumably due the basic hydrophobic motif present in all of these molecules. Following the discovery of a novel cyclohexyl azetidinylamide CCR2 antagonist scaffold, replacement of the amide bond with heterocyclic rings was explored as a strategy for reducing hERG binding and improving pharmacokinetic properties.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Azetidines/chemistry , Azetidines/pharmacology , Receptors, CCR2/antagonists & inhibitors , Animals , Humans , MiceABSTRACT
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG.
Subject(s)
Azetidines/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Hippurates/pharmacology , Receptors, CCR2/antagonists & inhibitors , Azetidines/chemical synthesis , Azetidines/chemistry , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/metabolism , Hippurates/chemical synthesis , Hippurates/chemistry , Humans , Molecular Structure , Receptors, CCR2/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.
Subject(s)
Amides/chemistry , Anti-Inflammatory Agents/chemistry , Receptors, CCR2/antagonists & inhibitors , Acute Disease , Administration, Oral , Amides/pharmacology , Amides/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Drug Evaluation, Preclinical , Humans , Inflammation/drug therapy , Mice , Mice, Transgenic , Rats , Receptors, CCR2/metabolism , Structure-Activity RelationshipABSTRACT
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.
Subject(s)
Factor Xa Inhibitors , Indazoles/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Caco-2 Cells , Cell Membrane Permeability , Crystallography, X-Ray , Factor Xa/chemistry , Humans , Hydrogen Bonding , In Vitro Techniques , Indazoles/chemistry , Indazoles/pharmacology , Microsomes, Liver/enzymology , Models, Molecular , Protein Conformation , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , ThermodynamicsABSTRACT
We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.
Subject(s)
Anticoagulants/chemical synthesis , Fibrinolytic Agents/chemical synthesis , Guanidines/chemical synthesis , Pyrazines/chemical synthesis , Thrombin/antagonists & inhibitors , Amino Acid Motifs , Animals , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Blood Pressure/drug effects , Caco-2 Cells , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Dogs , Double-Blind Method , Electrocardiography , Female , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Guanidines/pharmacokinetics , Guanidines/pharmacology , Guinea Pigs , Heart Rate/drug effects , Hemodynamics/drug effects , Humans , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Models, Molecular , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Thrombin/chemistry , Venous Thrombosis/blood , Venous Thrombosis/drug therapyABSTRACT
Through structure-based drug design and parallel synthesis, we have discovered a novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as guanidine bioisosteres. These compounds have been found to be highly potent, highly selective, and orally bioavailable.