ABSTRACT
The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
Subject(s)
Complement Factor D/antagonists & inhibitors , Complement Pathway, Alternative/drug effects , Proline/analogs & derivatives , Proline/pharmacology , Administration, Oral , Animals , Atypical Hemolytic Uremic Syndrome/drug therapy , Atypical Hemolytic Uremic Syndrome/immunology , Complement Factor D/immunology , Complement Membrane Attack Complex/antagonists & inhibitors , Complement Membrane Attack Complex/immunology , Female , Haplorhini , Humans , Macaca fascicularis , Macular Degeneration/drug therapy , Macular Degeneration/immunology , Male , Mice , Proline/administration & dosage , Proline/pharmacokineticsABSTRACT
Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 µmol/kg demonstrated significant reduction of brain Aß levels.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Brain/metabolism , Cyclic S-Oxides/chemical synthesis , Ethylamines/chemical synthesis , Sulfones/chemical synthesis , Animals , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Blood-Brain Barrier/metabolism , Cell Line , Cricetinae , Cricetulus , Crystallography, X-Ray , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , Dogs , Drug Design , Ethylamines/chemistry , Ethylamines/pharmacology , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Indazoles/pharmacology , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Mice , Mice, Transgenic , Models, Molecular , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which exhibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.
Subject(s)
Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/pharmacology , Sulfonamides/chemistry , Crystallography, X-Ray , Hydroxamic Acids/chemistry , Models, Molecular , Protease Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A synthesis of an antagonist of E-selectin previously reported by a group at Novartis Pharma in Basel is described. An important feature involves the formation of an ether linkage based on a Rh(II)-catalyzed reaction. Stereocontrolled glycosylations rely on the anomeric activation of 2-pyridylthio carbonate as leaving group for the attachment of beta-D-galactopyranosyl and alpha-L-fucopyranosyl units on a common 1,5-anhydro D-glucitol scaffold.
