ABSTRACT
A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aß1-42 and Aß1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aß1-37 and Aß1-38 were observed, with no change in the total amount of Aß1-x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.
ABSTRACT
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
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Guanidines/pharmacology , Macrocyclic Compounds/pharmacology , Proline/analogs & derivatives , Proline/pharmacology , Protease Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amyloid beta-Peptides/biosynthesis , Animals , Caco-2 Cells , Cathepsin D/antagonists & inhibitors , Cathepsin E/antagonists & inhibitors , Dogs , Guanidines/chemical synthesis , Humans , Macrocyclic Compounds/chemical synthesis , Madin Darby Canine Kidney Cells , Male , Mice , Molecular Docking Simulation , Pepsin A/antagonists & inhibitors , Proline/chemical synthesis , Protease Inhibitors/chemical synthesisABSTRACT
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Diamines/chemistry , Diamines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Alzheimer Disease/drug therapy , Animals , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Diamines/chemical synthesis , Diamines/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Mice , Mice, Knockout , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Lactams/chemistry , Lactams/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Animals , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Lactams/chemical synthesis , Lactams/pharmacokinetics , Mice , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
A series of Maxi-K openers for the treatment of erectile dysfunction based on the 3-thio-quinolinone core is described. Significant levels of channel opening (up to 550% of control) are seen in transfected oocytes. Functional activity in rabbit corpus cavernosum tissue strips confirms the potential to effect therapy for ED, the effect being maximal for the 3-amino-2-hydroxy thiol side chain.
