ABSTRACT
Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP-XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).
Subject(s)
Antineoplastic Agents/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Piperazines/pharmacology , X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , ERG1 Potassium Channel/antagonists & inhibitors , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Macaca fascicularis , Male , Mice, Inbred BALB C , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , X-Linked Inhibitor of Apoptosis Protein/chemistry , X-Linked Inhibitor of Apoptosis Protein/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
Subject(s)
Enzyme Inhibitors/pharmacology , Lactams/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Lactams/administration & dosage , Lactams/chemical synthesis , Lactams/chemistry , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Tissue DistributionABSTRACT
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Pyrazoles/pharmacology , Thiazoles/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Binding Sites/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.
ABSTRACT
Rhodium-bound nitrenoids are trapped by tethered allenes generating acyloxy-enamines, aminocyclopropanes, and methylene aziridines. The aminocyclopropanes undergo substitution of the acetoxy group by a variety of nucleophiles.
Subject(s)
Allyl Compounds/chemistry , Aziridines/chemistry , Rhodium/chemistry , Amination , Cyclization , Models, Molecular , Molecular Structure , Propane/chemistryABSTRACT
A series of 3-amino-6-aryl-pyridazines have been identified as CB(2) agonists with high efficacy and selectivity against the CB(1) receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Isoquinolines/chemical synthesis , Pyridazines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Pain/drug therapy , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
The unusual methylene aziridine 6-tert-butyl-3-oxa-2-thia-1-azabicyclo[5.1.0]oct-6-ene 2,2-dioxide, C(9)H(15)NO(3)S, was found to crystallize with two molecules in the asymmetric unit. The structure was solved in both the approximately orthogonal and the oblique settings of space group No. 14, viz. P2(1)/n and P2(1)/c, respectively. A comparison of these results clearly displayed an increase in the correlation between coordinates in the ac plane for the oblique cell. The increase in the corresponding covariances makes a significant contribution to the standard uncertainties of derived parameters, e.g. bond lengths. Since there is yet no CIF definition for the full variance-covariance matrix, there are clear advantages to reporting the structure in the nonstandard space-group setting.
Subject(s)
Aza Compounds/chemistry , Aziridines/chemistry , Oxides/chemistry , Crystallography, X-Ray , Models, Molecular , StereoisomerismABSTRACT
2-Amino-5-aryl-pyridines, exemplified by compound 1, had been identified as a synthetically tractable series of CB(2) agonists from a high-throughput screen of the GlaxoSmithKline compound collection. Described herein are the results of an investigation of the structure-activity relationships (SAR) which led to the identification a number of potent and selective agonists.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Drug Design , Molecular Structure , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
