Oscar Delgado

Stereochemical determination of dictyostatin, a novel microtubule-stabilising macrolide from the marine sponge Corallistidae sp.Electronic supplementary information (ESI) available: copies of 1D and 2D NMR spectra, tables of spectral data and calculated torsion angles. See http://www.rsc.org/suppdata/cc/b3/b316390c/

The relative stereochemistry of the 22-membered marine macrolide dictyostatin, a Taxol-like antimitotic agent, was determined based on a combination of extensive high field NMR studies, including J-based configuration analysis, and molecular modelling.

Concise Total Synthesis of the Thiazolyl Peptide Antibiotic GE2270 A

The potent antibiotic thiazolylpeptide GE2270 A was synthesized starting from N-tert-butyloxycarbonyl protected valine in a longest linear sequence of 20 steps and with an overall yield of 4.8 %. Key strategy was the assembly of the 2,3,6-trisubstituted pyridine core by consecutive cross-coupling reactions starting from 2,6-dibromo-3-iodopyridine. The complete Southern fragment was installed by Negishi cross-coupling of 3-zincated 2,6-dibromopyridine at the terminal 2-iodothiazole of a trithiazole (87 %). The substituent at C-6 representing the Northern part of the molecule was introduced in form of the truncated tert-butyl 2-bromothiazole-4-carboxylate after metalation to a zinc reagent by another Negishi cross-coupling (48 %). Decisive step of the whole sequence was the macrocyclization to a 29-membered macrolactam, which was conducted as an intramolecular Stille cross-coupling occurring at C-2 of the pyridine core and providing the desired product in 75 % yield. The required stannane was obtained by amide bond formation (87 %) between a complex dithiazole fragment representing the Eastern part of GE2270 A and a 3,6-disubstituted 2-bromopyridine. Final steps included attachment of a serine-proline amide dipeptide to the Northern part of the molecule (65 %), formation of the oxazoline ring and silyl ether deprotection (55 % overall).

1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimers disease.

Diastereoselective Synthesis of 2-Phenyl-3-(trifluoromethyl)piperazines as Building Blocks for Drug Discovery

The synthesis of enantiomerically pure cis- and trans-2-phenyl-3-(trifluoromethyl)piperazines is described. It involved, as the key step, a diastereoselective nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to α-amino sulfinylimines bearing Ellmans auxiliary. This methodology allows an entry into hitherto unknown trifluoromethylated and stereochemically defined piperazines, key scaffold components in medicinal chemistry.

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.

N-bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders

The search for novel heterobicyclic compounds within the drug-like chemical space continues to be an area of interest in medicinal chemistry. Unsaturated N-bridgehead heterocycles are well represented in marketed drugs for a variety of therapeutic areas, and continue to play an important role in central nervous system (CNS) drug discovery programs. Examples of medicinal chemistry strategies that make use of N-bridged 5,6-bicyclic pyridines are discussed here in this Minireview, which covers the literature from 2010 up to 2014. B1-class imidazopyridines and B3-class pyrazolopyridines have proven to be at the forefront of molecular prototypes that are capable of interacting with disease relevant targets in neurodegeneration and neuropsychiatry.