A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of ...structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure−activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a K i value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha 7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of ...previously disclosed alpha 7 nAChR agonist, PNU- 282,987, while maintaining the compounds other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new ...therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure−activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C−C or N−C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the α7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously ...disclosed α7 nAChR agonist, PNU-282,987, while maintaining the compound’s other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (
1h,
1o,
2a,
9a, and
18a) shows an improved hERG safety profile over PNU-282,987.
An efficient stereoselective total synthesis of the furo2,3-cpyridine thiopyrimidine HIV-1 reverse transcriptase inhibitors, PNU-142721 and PNU-109886, has been developed. A convergent approach was ...utilized, providing direct access to the desired (S)-configuration of the molecule by making use of the alkylation of 4-amino-6-chloro-2-thiopyrimidine with the appropriate (R)-1-chloroethyl furo2,3-cpyridine intermediates. The successful preparation makes use of an efficient enzymatic kinetic resolution of the key 1-hydroxyethyl furo2,3-cpyridine intermediates to establish stereochemical control of the respective stereogenic centers. In addition, a workable asymmetric reduction strategy was developed for the synthesis of PNU-109886. Prudent reagent selection for the chlorination required for the final coupling reactions allowed for maintenance of the stereochemical integrity of the target compounds. Structural assignment of the absolute configuration of PNU-142721 and PNU-109886 as the (S)-enantiomer was confirmed by X-ray crystallographic analysis.
As part of medicinal chemistry efforts we found it necessary to develop general syntheses of highly enantiomerically enriched 1-aryl-2-chloroethanols and 1-aryl-2-methylaminoethanols. A survey of ...literature methods suggested that a truly general approach had not yet been reported, encouraging us to undertake the development of such a methodology. This study describes the design, development, and reduction to practice of a general synthesis of chiral 1-aryl-2-chloroethanols and the transformation of these entities to highly enantiomerically enriched 1-aryl-2-methylaminoethanols. Of particular importance were observations of the impact of solvent and the method of catalyst preparation on the yield and enantiomerical excess of chlorohydrins prepared via Noyori transfer hydrogenations of aryl-chloromethyl ketones.
The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover ...non-peptidic HIV protease inhibitors previously identified compound I (phenprocoumon, K i = 1 μM) as a lead template. Structure-based design of potent non-peptidic inhibitors, utilizing crystal structures of HIV protease/inhibitor complexes, provided a rational basis for the previously reported carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones. The amino acid containing compound V (K i = 4 nM) provided an example of a promising new series of HIV protease inhibitors with significantly improved enzymatic binding affinity. In this report, further structure−activity relationship studies, in which the carboxamide is replaced by a sulfonamide functionality, led to the identification of another series of nonamino acid containing promising inhibitors with significantly enhanced enzyme binding affinity and in vitro antiviral activity. The most active diastereomer of the sulfonamide-containing pyrone XVIII (K i = 0.5 nM) shows improved antiviral activity (IC50 = 0.6 μM) and represents an example of a new design direction for the discovery of more potent non-peptidic HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.
The imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo4,5,1-ijquinolin-5-amine (R)-3 is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro ...binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo4,5,1-ijquinolin-2(1H)-one (R)-6; intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3−6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a ...strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 μg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of α-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.
The design, synthesis, and antibacterial activity profile of a series of new oxazolidinones are discussed.
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