Protein phosphatases have recently emerged as important targets for research in chemical biology and medicinal chemistry, and new classes of phosphatase inhibitors are in high demand. BIOS (biology-oriented synthesis) employs the criteria of relevance to nature and biological prevalidation for the design and synthesis of compound collections. In an application of the BIOS principle, an efficient solid-phase synthesis of highly substituted indolo[2,3-a]quinolizidines by using a vinylogous Mannich-Michael reaction in combination with phosgene- or acid-mediated ring closure was developed. Screening of this library for phosphatase inhibitors yielded a new inhibitor class for the Mycobacterium tuberculosis phosphatase MptpB.
Recently, we developed a concept known as biology-oriented synthesis (BIOS), which targets the design and synthesis of small- to medium-sized compound libraries on the basis of genuine natural product templates to provide screening compounds with high biological relevance. We herein describe the parallel solution phase synthesis of two BIOS-based libraries starting from alpha-santonin (1). Modification of the sesquiterpene lactone 1 by introduction of a thiazole moiety followed by a Lewis-acid-mediated lactone opening yielded a first library of natural product analogues. An acid-mediated dienone-phenol rearrangement of 1 and a subsequent etherification/amidation sequence led to a second natural product-based library. After application of a fingerprint-based virtual screening on these compounds, the biological screening of 23 selected library members against 5-lipoxygenase resulted in the discovery of four potent novel inhibitors of this enzyme.
We here report the discovery and early characterization of Compound 3, a representative of a novel class of small molecule bradykinin (BK) B 2 receptor antagonists, and its superior profile to the prior art B 2 receptor antagonists Compound 1 and Compound 2. Compound 3, Compound 2, and Compound 1 are highly potent antagonists of the human recombinant B 2 receptor (K b values 0.24, 0.95, and 1.24 nM, respectively, calcium mobilization assay). Compound 3 is more potent than the prior art compounds and icatibant in this assay (K b icatibant 2.81 nM). The compounds also potently inhibit BK-induced contraction of endogenous B 2 receptors in a human isolated umbilical vein bioassay. The potencies of Compound 3, Compound 2, Compound 1, and icatibant are (pA 2 values) 9.67, 9.02, 8.58, and 8.06 (i.e. 0.21, 0.95, 2.63, and 8.71 nM), respectively. Compound 3 and Compound 2 were further characterized. They inhibit BK-induced c-Fos signaling and internalization of recombinant human B 2 receptors in HEK293 cells, and do not antagonize the venous effects mediated by other G protein-coupled receptors in the umbilical vein model, including the bradykinin B 1 receptor. Antagonist potency of Compound 3 at cloned cynomolgus monkey, dog, rat, and mouse B 2 receptors revealed species selectivity, with a high antagonist potency for human and monkey B 2 receptors, but several hundred-fold lower potency for the other B 2 receptors. The in vitro off-target profile of Compound 3 demonstrates a high degree of selectivity over a wide range of molecular targets, including the bradykinin B 1 receptor. Compound 3 showed a lower intrinsic clearance in the microsomal stability assay than the prior art compounds. With an efflux ratio of 1.0 in the Caco-2 permeability assay Compound 3 is predicted to be not a substrate of efflux pumps. In conclusion, we discovered a novel chemical class of highly selective and very potent B 2 receptor antagonists, as exemplified by Compound 3. The compound showed excellent absorption in the Caco-2 assay, predictive of good oral bioavailability, and favourable metabolic stability in liver microsomes. Compound 3 has provided a significant stepping stone towards the discovery of the orally bioavailable B 2 antagonist PHA-022121, currently in phase 1 clinical development.
The synthesis of the natural siderophore myxochelin B (1S) and its enantiomer 1R is described. 1S and 1R served as precursors for the synthesis of new hexadentate siderophores, the myxochelins C (7S) and CR (7R), D (14S) and DR (14R), E (19S) and (RS)‐F (26R, S), with 2,3‐dihydroxybenzoate (DHB) ligands and the simple backbones of asymmetric 1,2,n‐triamino‐n‐alkanes. For the myxochelins C, D, E and F n is 6 (from lysine), 5 (from ornithin), 4 (from asparagine amide) and 7 [from (±)‐2‐aminopimelic acid], respectively. The additional amino functions in the starting compounds were provided by dehydration of the corresponding primary amides, and subsequent reduction of the nitriles by cobalt boride in methanol. All new siderophores supply bacteria with ferric ions with an efficiency which depends on their chain length and stereochemistry. They show significant activity against the cytomegalo virus.
The generation of a natural-product-based library starting from andrographolide is described. Utilizing andrographolide itself in parallel solution-phase synthesis leads to a 360-membered library. The initial transformation of the starting material via ozonolysis is followed by the conversion into a suitable template by introduction of a thiazole moiety. Subsequent decoration at two points of diversity yields the desired natural product derivatives. The selection of actually synthesized compounds is based on a virtually generated library and the assessment of its members with respect to physicochemical parameters, thus ensuring pharmacological relevance of the compounds.
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