Anna Quattropani

In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties.

Non-competitive N-methyl-d-aspartate (NMDA) blockers induce schizophrenic-like behavior in healthy volunteers and exacerbate symptomatology in schizophrenic patients. Hence, a compound able to enhance NMDA neurotransmission by increasing levels of d-serine, an endogenous full agonist at the glycine site of the NMDA receptors, could have anti-psychotic activity. One way to increase d-serine levels is the inhibition of d-amino acid oxidase (DAAO), the enzyme responsible for d-serine oxidation. Indeed AS057278, a potent in vitro (IC(50)=0.91 microM) and ex vivo (ED(50)=2.2-3.95 microM) DAAO inhibitor, was able to increase d-serine fraction in rat cortex and midbrain (10 mg/kg i.v.). AS057278 was able to normalize phencyclidine (PCP)-induced prepulse inhibition after acute (80 mg/kg) and chronic (20 mg/kg b.i.d.) oral administration in mice. Finally, AS057278 after oral chronic treatment (10 mg/kg b.i.d.) was able to normalize PCP-induced hyperlocomotion. These results suggest that AS057278 has the potential to anti-psychotic action toward both cognitive and positive symptoms of schizophrenia.

Planar chiral arene tricarbonylchromium complexes via enantioselective deprotonation / electrophile addition reactions

Sequential reaction of prochiral (η6-arene)Cr(CO)3 complexes with chiral amide bases and electrophiles yielded planar chiral complexes. Benzaldehyde acetal and phenyl carbamate complexes gave o-substituted products with 64 to 81% enantiomeric excess. With the benzaldehyde acetal complex, competitive benzylic deprotonation occurred. Enantiomeric purity of the substituted carbamate complexes could be increased to > 90% ee by fractional crystallization. The racemate crystallized selectively, leaving the enantiomerically enriched complex in solution.

Enantioselective Deprotonation/Electrophile Addition Reactions of Tricarbonyl(phenyl carbamate)chromium Complexes

Sequential reaction of the tricarbonyl[(?6-phenyl) carbamate]chromium complex 3 with chiral amide bases (see 4 and 5) and electrophiles yielded planar chiral ortho-substituted complexes 6 with up to 70% enantiomeric excess (ee) (Scheme 2, Table 1 and 2). The enantiomer purity could be increased to >90% ee by fractional crystallization. In all but one case the racemate crystallized selectively, leaving the enantiomerically enriched complex in solution. X-Ray crystal-structure analyses of rac-6a and (1R)-6a suggest that this can be ascribed to a more favorable packing of enantiomers of opposite configuration in the solid state than that of the enantiomerically pure solid. Increasing the temperature of the intermediate ortho-lithiated aryl carbamate complex induced an anionic ortho-Fries rearrangement: The 1,3-transposition of the carbamoyl group yielded the ortho-substituted (?6-benzamide)tricarbonylchromium complexes 10 in 65% yield, after exposure to the electrophile (Scheme 6), and the use of a chiral amide base 5 in the deprotonation step afforded the product with an ee of 54%.

Chiral CO-emulating ligands: From arene chromium chemistry to enantioselective catalysis

A one pot nucleophile/electrophile additiodhydrogenation sequence was applied to ((benzene)Cr(CO)j) to give predominantly the 4,5-trans-disubstituted cy- clohexene. Several asymmemc modifications of the sequential addition of C-nu- cleophiles and C-elecuophiles to (arene)Cr(CO), complexes are discussed. A mechanistically intriguing route involves the use of chiral phosphorous ligands to control the diastereoselectivity in the migratory CO insertion step and/or the reductive elimination step in the sequence. Ephedrine and norephedrine derived ligands gave product ee of up to 69 9%. New C2-chiral bidentate ligands (L*) which emulate some of the bonding characteristics of CO were synthesized and briefly considered for this application. The main interest in these ligands concerns their potential in catalytic C-C bond forming reactions; a first application to the Lewis acid (CpFeL*)+ catalyzed Diels- Alder reaction between enals and dienes was successfully realized.

Regioselective synthesis of 2,8-disubstituted 4-aminopyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester compounds.

We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through S(N)Ar and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünigs base and C-2 addition in (i)PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki-Miyaura reaction and the sulfanyl group by Liebeskind-Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-d]pyrimidine derivatives, with various substituents.

Photocycloaddition of Arenes and Allenes

In this work, we report on a new intramolecular para cycloaddition of arenes with allenes, yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity. Bicyclo[2.2.2]octadiene-type products and benzoxepine acetals are formed in this reaction, in ratios and yields depending on the substitution pattern on the aromatic ring, the nature of the chromophore, and the tether. This unprecedented reaction has remarkable features that distinguish it from many other photochemical transformations: it is particularly robust with respect to substituents, it can be scaled up without a notable loss of efficiency, and it can lead to structures with a high degree of complexity in low to good yields. All photochemical precursors could be synthesized readily in three steps. We confirmed the compatibility of the nitrogen atom in the photocycloaddition step, which gives access to a bicyclo[2.2.2]octadiene scaffold with two points that allow further diversification. This reaction was scaled up to multigram quantities without erosion of the typically high yields in photocycloadducts. Sequential deprotection of the N- or C-terminus of bicyclic amino acids gave access to two conformationally constrained unnatural amino acids with different dispositions of the two anchor points.

Access and regioselective transformations of 6-substituted 4-aryl-2,8-dichloropyrido[3,2-d]pyrimidine compounds.

We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido[3,2-d]pyrimidines 1 with R(1) substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind-Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido[3,2-d]pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S(N)Ar reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S(N)Ar, Suzuki-Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind-Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of 1 was developed, thereby providing an efficient approach to explore the structure-activity relationship of pyrido[3,2-d]pyrimidine derivatives such as 9, 10, 15, and 16.

An Efficient and Expeditious Synthesis of Di- and Trisubstituted Amino-phenyl and -benzyl Derivatives of Tetrazole and [1,3,4]Oxadiazol-2-one

A practical protocol for the parallel synthesis and purification of amino tetrazole and [1,3,4]oxadiazol-2-one derivatives as carboxylic acid bioisosteres is described. Phenyl- and benzyl-amines, substituted with tetrazole or [1,3,4]oxadiazol-2-one, were transformed into functionally diverse and novel compounds, with p K a values ranging from 4.9 to 8.4, by two sequential reductive alkylation reactions. These series of di- and trisubstituted amino-phenyl and -benzyl derivatives were produced in solution using solid-supported reagents and were purified by solid-phase extraction (SPE) techniques.

Novel non-carbohydrate O-GlcNAcase inhibitors with CNS drug properties as potential treatment for Alzheimer’s disease and tauopathies

Novel non-carbohydrate O-GlcNAcase inhibitors with CNS drug properties as potential treatment for Alzheimer’s disease and tauopathies Heike Hering, Danielle Graham, Solenne Ousson, Maud Neny, Audrey Gray, Brandy Giacomozzi, John Joyce, Vikram Dutt, Michael Busch, Andrew Cameron, Leslie Liu-Bujalski, Henry Yu, Hui Tian, Mark Shearman, Anna Quattropani, Bruno Permanne, Christoph Wiessner, Dirk Beher

Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids

Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (K i < 10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C19 > 1 μM). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development.