ABSTRACT
This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.
Subject(s)
Drug Discovery , Pyrimidines/pharmacology , Receptor, Muscarinic M4/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptor, Muscarinic M4/metabolism , Structure-Activity RelationshipABSTRACT
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.
Subject(s)
Receptor, Muscarinic M4/chemistry , Allosteric Regulation , Amides/chemistry , Azetidines/chemistry , Benzene/chemistry , Molecular Structure , Protein Binding , Pyrazines/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
Subject(s)
Drug Discovery , Heterocyclic Compounds, 2-Ring/pharmacology , Isoquinolines/pharmacology , Myotonin-Protein Kinase/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation/drug effects , Dose-Response Relationship, Drug , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Isoquinolines/chemistry , Molecular Structure , Myotonin-Protein Kinase/metabolism , Structure-Activity RelationshipABSTRACT
This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Subject(s)
Aldehyde Oxidase/metabolism , Myotonia Congenita/metabolism , Receptor, Muscarinic M4/metabolism , Animals , Drug Discovery , Humans , Rats , Structure-Activity RelationshipABSTRACT
This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.
Subject(s)
Piperidines/pharmacology , Pyrimidines/pharmacology , Quinazolines/pharmacology , Receptor, Muscarinic M4/metabolism , Thiophenes/pharmacology , Allosteric Regulation , Animals , Brain/drug effects , Brain/metabolism , Humans , Microsomes, Liver/metabolism , Piperidines/chemical synthesis , Piperidines/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Quinazolines/chemical synthesis , Quinazolines/metabolism , Rats , Receptor, Muscarinic M4/agonists , Receptor, Muscarinic M4/antagonists & inhibitors , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/metabolismABSTRACT
beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.
Subject(s)
Amides/chemical synthesis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Isonicotinic Acids/chemical synthesis , Peptide Fragments/metabolism , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Brain/metabolism , Dose-Response Relationship, Drug , Isonicotinic Acids/pharmacokinetics , Isonicotinic Acids/pharmacology , Mice , Rats , Structure-Activity RelationshipABSTRACT
We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemical synthesis , Sulfonamides/chemical synthesis , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases/chemistry , Binding Sites , Cell Line , Cell Membrane Permeability , Crystallography, X-Ray , Drug Design , Ethylamines/chemistry , Ethylamines/pharmacology , Humans , Models, Molecular , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Crystallography, X-Ray , Kinetics , Models, Molecular , Molecular ConformationABSTRACT
A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.