ABSTRACT
(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford ß-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Fluoroquinolones/chemistry , Fluoroquinolones/pharmacology , Nitriles/chemistry , Nitriles/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/chemical synthesis , Catalysis , Molecular Structure , StereoisomerismABSTRACT
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Subject(s)
Cicatrix/prevention & control , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Skin/drug effects , Animals , Models, Molecular , Phosphorylation , Rats , Receptor, Transforming Growth Factor-beta Type IABSTRACT
A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.
Subject(s)
Anti-Bacterial Agents , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Quinazolinones , Topoisomerase II Inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Combinatorial Chemistry Techniques , Fluoroquinolones/chemical synthesis , Fluoroquinolones/chemistry , Fluoroquinolones/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Quinazolinones/pharmacology , Structure-Activity RelationshipABSTRACT
The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Quinazolinones/chemical synthesis , DNA Topoisomerase IV/antagonists & inhibitors , Drug Resistance, Multiple, Bacterial/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Methicillin Resistance , Microbial Sensitivity Tests , Structure-Activity Relationship , Topoisomerase II InhibitorsABSTRACT
A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s, with exceptional enzyme potency (IC50 = 0.2 microM) and activity against gram-positive organisms (MIC's = 0.015-0.06 microg/mL).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Topoisomerase II Inhibitors , Amines/chemistry , Amines/pharmacology , Anti-Bacterial Agents/chemistry , DNA Gyrase , Gram-Positive Bacteria/drug effects , Inhibitory Concentration 50 , Quinazolinones/chemistry , Structure-Activity RelationshipABSTRACT
A series of 3-hydroxyquinazoline-2,4-diones was synthesized and evaluated for antibacterial activity. This series represents a novel addition to the DNA gyrase inhibitor class of antibacterials. Appropriate substitutions onto the core template yielded compounds with excellent potency against E. coli gyrase and significant in vitro Gram-negative and Gram-positive antibacterial activity.