ABSTRACT
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Subject(s)
Chemistry, Pharmaceutical/methods , Urotensins/antagonists & inhibitors , Administration, Oral , Animals , Brain/metabolism , Chromatography, High Pressure Liquid , Diamines/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Receptors, Opioid, kappa/chemistry , Stereoisomerism , Structure-Activity Relationship , Urotensins/chemistryABSTRACT
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Subject(s)
Aniline Compounds/pharmacology , Piperidones/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Administration, Oral , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Animals , Biological Availability , Cell Line , Drug Evaluation, Preclinical , Humans , Molecular Structure , Molecular Weight , Piperidones/chemical synthesis , Piperidones/chemistry , Rats , Small Molecule Libraries , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Phenylbutyrates/pharmacology , Phenylbutyrates/pharmacokinetics , Acetates/chemistry , Administration, Oral , Aminopyridines/chemistry , Animals , Biological Availability , Cell Adhesion/drug effects , Cell Line , Half-Life , Humans , Phenylbutyrates/chemistry , RatsABSTRACT
Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
Subject(s)
Anti-Bacterial Agents , Enzyme Inhibitors , Oxidoreductases/antagonists & inhibitors , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Multiple, Bacterial , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Humans , Male , Microbial Sensitivity Tests , Rats , Rats, Sprague-Dawley , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymology , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/enzymology , Structure-Activity RelationshipABSTRACT
Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.
