ABSTRACT
Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aß42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aß42 in rats treated with a 30 mg/kg oral dose.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Alkenes/chemistry , Alkenes/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Binding Sites/physiology , HEK293 Cells , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/cerebrospinal fluid , Rats , Structure-Activity RelationshipABSTRACT
Herein we describe structure-activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4- and 6-positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.
Subject(s)
Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Humans , Kinetics , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Tissue DistributionABSTRACT
We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2â³ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aß40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aß in nonrodent preclinical species.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Drug Design , Heterocyclic Compounds/chemistry , Imines/chemistry , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Cerebral Cortex/metabolism , Enzyme Inhibitors/pharmacology , Macaca fascicularis , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aß40 levels upon subcutaneous and oral administration to rats.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/therapeutic use , Aspartic Acid Endopeptidases/therapeutic use , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Drug Design , Drug Discovery , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aß(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Nitriles/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidinones/chemical synthesis , Thiophenes/chemical synthesis , Administration, Oral , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cerebral Cortex/metabolism , Crystallography, X-Ray , HEK293 Cells , Humans , Macaca fascicularis , Models, Molecular , Molecular Conformation , Nitriles/pharmacokinetics , Nitriles/pharmacology , Peptide Fragments/metabolism , Permeability , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Quantum Theory , Rats , Stereoisomerism , Structure-Activity Relationship , Thermodynamics , Thiophenes/pharmacokinetics , Thiophenes/pharmacologyABSTRACT
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Imines/chemistry , Imines/therapeutic use , Peptide Fragments/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Humans , Imines/pharmacokinetics , Mice , Mice, Transgenic , Peptide Fragments/antagonists & inhibitors , Rats , Structure-Activity RelationshipABSTRACT
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Subject(s)
Benzazepines/chemistry , Benzazepines/pharmacology , Dopamine Antagonists/chemistry , Dopamine Antagonists/pharmacology , Receptors, Dopamine D1/antagonists & inhibitors , Animals , Rats , Receptors, Dopamine D1/physiologyABSTRACT
A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Hydroxamic Acids/pharmacology , Protease Inhibitors/pharmacology , ADAM17 Protein , Animals , Area Under Curve , Biological Availability , Drug Discovery , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacokinetics , Models, Molecular , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
[reaction: see text] Bridged bicyclic dienones underwent silyl-directed Nazarov cyclization with generally very high diastereoselectivity. In most cases, a strong preference for cyclization to the product with an exo-disposed cyclopentenone was seen. However, the presence of additional unsaturation in the three-carbon bridge of a bicyclo[3.2.1]octadiene system caused complete reversal in selectivity with exclusive formation of the endo-cyclopentenone. The observed selectivities are believed to result from a combination of steric and electronic effects.
