André Alker

Characterization of the two major CYP450 metabolites of ozonide (1,2,4-trioxolane) OZ277

The antimalarial synthetic ozonide OZ277 (RBx11160) was hydroxylated by human liver microsomes at the distal bridgehead carbon atoms of the spiroadamantane substructure to form two carbinol metabolites devoid of antimalarial activity.

Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists.

SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo.

Efficient One-Pot Synthesis of the GABAB Positive Allosteric Modulator (R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one

Abstract The GABAB positive allosteric modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (1) was synthesized in one pot from the anhydrous lithium salt of 2,4-di-tert-butylphenol and methyl trifluoropyruvate mediated by a stoichiometric amount of anhydrous gallium(III) chloride in 64% overall yield. The enantiomers of 1 were separated by chiral-phase HPLC (Chiralpak AD®), and the absolute configuration was determined by X-ray crystallography.

Oxetane δ‐Amino Acids: Chemoenzymatic Synthesis of 2,4‐Anhydro‐5‐N‐(t‐butoxycarbonyl)amino‐D‐lyxonic Acid

Starting from 1,2‐O‐isopropylidene‐D‐xylose, methyl 2,4‐anhydro‐3,5‐di‐O‐benzyl‐D‐lyxonate (4) was synthesized. Debenzylation and transformation of the primary hydroxyl group yielded methyl 2,4‐anhydro‐5‐N‐(t‐butoxycarbonyl)amino‐D‐lyxonate (9). While transesterification of 4 under basic reaction conditions was straightforward, an analogous reaction with 9 was not successful. After screening of several lipases, the enzymatic transesterification of 9 was achieved with lipase L2 from Candida antarctica to furnish the title compound 2,4‐anhydro‐5‐N‐(t‐butoxycarbonyl)amino‐D‐lyxonic acid in excellent yield. The stereochemistry at the oxetane ring was proven by an x‐ray structure of the intermediate methyl 2,4‐anhydro‐5‐azido‐D‐lyxonate.

Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.

Inappropriately high levels of aldosterone are associated with many serious medical conditions, including renal and cardiac failure. A focused screen hit has been optimized into a potent and selective aldosterone synthase (CYP11B2) inhibitor with in vitro activity against rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity factor of 160 against cytochrome CYP11B1 in the last species. The novel tetrahydroisoquinoline compound (+)-(R)-6 selectively reduced aldosterone plasma levels in vivo in a dose-dependent manner in db/db mice and cynomolgus monkeys. The selectivity against CYP11B1 as predicted by cellular inhibition data and free plasma fraction translated well to Synacthen challenged cynomolgus monkeys up to a dose of 0.1 mg kg(-1). This compound, displaying good in vivo potency and selectivity in mice and monkeys, is ideally suited to perform mechanistic studies in relevant rodent models and to provide the information necessary for translation to non-human primates and ultimately to man.

Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.

During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.

Libraries on Oxetane δ-Amino Acid Scaffolds: Syntheses and Evaluation of Physicochemical and Metabolic Properties

Oxetane δ-amino acids were investigated as scaffolds to generate oxetane-based libraries. As pharmacophores, oxadiazoles and triazoles were built up on the scaffolds. Important physicochemical properties of target compounds were predicted in silico, and some physicochemical (solubility, logD, pKa values, permeation through artificial membranes) and metabolic (intrinsic clearance) properties were determined experimentally. The compounds synthesized exhibited the desired ADMETox properties. From an in silico point of view, this work adds valuable information for the refinement of prediction tools.

Two distinct conformations of GABA locked by embedding in the bicyclo[3.1.0]hexane core structure.

Bicyclo[3.1.0]hexane and diverse heteroanalogues containing nitrogen, oxygen, or sulfur atoms in the five-membered ring have been recognized as interesting core structures of small molecules with diverse biological activities. They have been used as conformationally locked analogues of nucleoside building blocks and as intrinsically interesting building blocks in numerous other applications. They have been reported as intermediates in natural compound synthesis, or as constituents of bioactive compounds, 19] novel materials, and catalysts. Methanoproline 1, a naturally occurring inhibitor of proline metabolism, and 3-azabicyclo[3.1.0]hex-6-ylamine 2, a constituent of the potent broad-spectrum antibiotic trovafloxacin, are particularly prominent examples. They led to the design of the hybrid structure 3 as a conformationally locked basic amino acid analogue. Other ways to embed amino acid units such as glutamate into the bicyclo[3.1.0]hexane scaffold are illustrated by structure 4 or its corresponding 2-oxaand 2-thia-analogues 5 and 6 (Figure 1). Such compounds or further functionalized derivatives have been described by various research groups 22] and have resulted in highly potent metabotropic glutamate receptor antagonists or agonists. In all these examples, an extended conformation of the glutamate moiety was attempted and achieved. To the best of our knowledge, the prototypic 2aminobicyclo[3.1.0]hexane-6-carboxylic acid 7 a and its C2 epimer 8 a have not yet been prepared. Both contain an embedded g-aminobutyric acid (GABA) unit. Based on the structural results obtained for the bicyclic glutamate analogues, 6, 7] the GABA unit in 7 a,b should be locked in a fully extended conformation. In contrast, the corresponding C2 epimer 8 a,b should lock the GABA unit in a distinctly different conformation, depending on the conformational robustness of the bicyclic core system. A bicyclo[3.1.0]hexane core structure with or without embedded heteroatoms in the five-membered ring could, in principle, adopt three distinct conformations. An envelope conformation with an essentially planar five-membered ring (see Figure 2 b) is typically encountered for five-membered rings with conjugated exocyclic double bonds (e.g. , lactones, lactams, anhydrides, imides). For saturated (hetero)bicyclo[3.1.0] systems, five-membered ring envelope conformations are expected due to the structural constraints by the annelated cyclopropane unit (exerting a similar constraint as an endocyclic double bond), with the flap either anti (chair-type, Figure 2 a) or syn (boat-type, Figure 2 c) to the cyclopropane unit.

ITERATIVE ONE POT REACTIONS OF A CHIRAL SULFAMIDATE WITH 2,4,6-TRICHLOROPYRIDINE: REGIOCONTROLLED SYNTHESIS OF LINEAR AND ANGULAR CHIRAL DIPYRROLIDINO PYRIDINES

The product of the ring opening of a chiral sulfamidate with the 3- lithiopyridine species obtained by deprotonation of 2,4,6-trichloropyridine with n- BuLi can be deprotonated again in situ with n-BuLi and reacted with a second equivalent of the sulfamidate furnishing a bis -aminoethyl pyridine derivative which can be cyclized regioselectively to linear or angular chiral dipyrrolidino pyridines.