Reto Naef

Quinazolines: Combined type 3 and 4 phosphodiesterase inhibitors

A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3/4 inhibitors and are expected to have a therapeutic potential.

Isolation and synthesis of a novel immunosuppressive 17α-substituted dammarane from the flour of the Palmyrah palm (Borassus flabellifer)

The novel triterpene 1 with a dammarane skeleton and a hitherto unknown 17alpha-substitution pattern has been isolated from the Palmyrah palm in low yield and prepared by synthesis in larger quantities. 1 was shown to be an extremely potent immunosuppressant in vitro (MLR; IC50 = 10 ng/ml) and in vivo (DTH; ED50 = 0.01 mg/kg p.o.). A glucocorticoid like activity is excluded.

NEW 1-AMINO-1,2-DIPHENYLETHANOLS AS LIGANDS FOR THE ENANTIOSELECTIVE ADDITION OF ALKYLLITHIUMS TO BENZALDEHYDE

Abstract In the presence of equimolar amounts of lithium alkoxides derived from N -substituted 2-amino-1,2-diphenyl-ethanols, alkyllithium reagents add to benzaldehyde to furnish optically active secondary alcohols with enantiomeric excesses of up to 86%. The best results were obtained using the N -isopropyl- N -methyl substituted amino-alcohol.

8-Aryl xanthines potent inhibitors of phosphodiesterase 5.

In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.

Disease activated drugs: a new concept for the treatment of asthma

Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs, which have a proven efficacy for the treatment of the target disease. In opposition to pro-drugs, DAD are activated in inflamed but not normal tissues. Due to the disease specific activation, the amount of locally released drug(s) should be related directly to the severity of the inflammation. To test this concept in asthma a PDE4 inhibitor, an isoquinoline derivative, was chemically derivatized into pro-drugs or combined with corticosteroids. These new compounds were more readily cleaved into active PDE4 inhibitor, in bronchoalveolar lavage fluid (BALF) from Brown-Norway rats with lung inflammation than in BALF from rats without airway inflammation. The DAD concept (local selective release and improved therapeutic window) was validated in vivo using the inhibition of methacholine induced bronchoconstriction in guinea pigs with or without ozone induced lung inflammation. An example of DAD hydrolysis (isoquinoline-dexamethasone) was also examined in BALF from asthmatics and healthy volunteers.