Ashis K. Saha

Novel antifungals based on 4-substituted imidazole: a combinatorial chemistry approach to lead discovery and optimization.

A series of 4-substituted imidazole sulfonamides has been prepared by solid-phase chemistry. These compounds were found to have good in vitro antifungal activity and constitute the first examples of C-linked azoles with such activity. The most potent inhibitor (30) demonstrated inhibition of key Candida strains at an in vitro concentration of < 100nM and compared favorably with in vitro potency of itraconazole.

Novel antifungals based on 4-substituted imidazole: solid-phase synthesis of substituted aryl sulfonamides towards optimization of in vitro activity.

The in vitro activity of novel 4-substituted imidazole antifungals was optimized by solid-phase chemistry and parallel synthesis. Potent yeast-selective as well as broad-spectrum antifungal compounds (32 and 20) were discovered.

Achiral internucleoside linkages: CH2-CH2-NH and nH-CH2-CH2 linkages

The synthesis of CH2-CH2-NH and NH-CH2-CH2 internucleoside linkages are described. Antisense oligonucleosides containing these dimer modifications hybridized to the sense sequence. Furthermore incorporation of these backbone modifications enhanced the nuclease resistance of the antisense strand.

Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists.

In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.

Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists.

In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.

CD45 protein tyrosine phosphatase: Determination of minimal peptide length for substrate recognition and synthesis of some tyrosine-based electrophiles as potential active-site directed irreversible inhibitors

Abstract Using fyn PTK as a template, a series of phosphopeptides 1–11 spanning in length from 1–14 amino acids was prepared. Kinetic evaluation of 1–11 suggest that CD45 does not have a strong preference for its N- or C-terminal amino acids and that extended phosphopeptides are not required for efficient substrate turnover.

Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists.

In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.

Achiral internucleoside linkages 3: CH2NHCH2 linkage

Abstract A stereoselective method for the synthesis of 3′-α-or 3′-β-carbon substituted pyrimidine nucleosides was developed. The synthesis of the CH 2 NHCH 2 linkage is described. The linkage offers enhanced resistance to 3′-exonuclease.