ABSTRACT
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Indoles/chemical synthesis , Drug Design , Humans , Structure-Activity RelationshipABSTRACT
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aniline Compounds/chemistry , Triazoles/chemistry , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Aniline Compounds/chemical synthesis , Aniline Compounds/metabolism , Animals , Brain/metabolism , Drug Design , Humans , Mice , Mice, Transgenic , Protein Binding , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/metabolismABSTRACT
The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical γ-secretase modulatory profile by lowering Aß42 and Aß40 levels combined with an especially pronounced increase in Aß38 and Aß37 levels while leaving the total levels of amyloid peptides unchanged.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Benzimidazoles/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Amyloid beta-Peptides/metabolism , Animals , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Benzoxazoles/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Dogs , Drug Design , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Mice , Microsomes, Liver/metabolism , Molecular Conformation , Peptide Fragments/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Three analogues of 1a,25-dihydroxyvitamin D(3) (calcitriol), featuring a trans-fused decalin C,D-core with local S(2)-symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4aR,8aS)-octahydronaphthalene-1,5-dione (7). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity.
Subject(s)
Calcitriol , Calcitriol/analogs & derivatives , Calcitriol/chemical synthesis , Calcitriol/chemistry , Molecular Structure , Vitamins/chemical synthesis , Vitamins/chemistryABSTRACT
A short and high yielding route for the preparation of the title compound, starting from commercially available 1,5-dihydroxynaphthalene, is described. The key step in the sequence is the air oxidation of a bis(trimethylsilyloxy)diene precursor.
Subject(s)
Tetrahydronaphthalenes/chemical synthesis , Chromatography, Thin Layer , Molecular Structure , Tetrahydronaphthalenes/chemistryABSTRACT
During a 20-year collaboration the laboratories of UGent and KU Leuven have developed different series of Vitamin D analogs characterized by structural modifications in the central CD-ring system. Modifications have first involved the introduction of substituents at C11 and the epimerization at C14, and subsequently more drastic changes consisting in both ring deletion and enlargement relative to the natural CD-ring system. Lately, the focus has shifted towards the synthesis of analogs featuring a symmetrical CD-ring core. As an illustration two different series are presented.
