Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.

Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.

Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties.

Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.

Synthesis and evaluation of carbon-linked analogs of dual orexin receptor antagonist filorexant.

Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.

Recent patents regarding the discovery of small molecule CXCR4 antagonists.

BACKGROUND: The chemokine receptors, CCR(5) and CXCR(4), are the primary co-receptors responsible for mediating HIV-1 cell entry. Small molecules that antagonize these receptors utilize a fundamentally different approach for controlling viral replication than most other classes of antiretroviral agents in that they act on host cell factors rather than viral enzymes. Although CCR(5) modulators that demonstrate efficacy in the clinic against HIV have now become available, CXCR(4) antagonist development is at present at a more nascent stage. Due to the ability of HIV to switch between CCR(5) and CXCR(4) entry co-receptors, the development of a CXCR(4) antagonist is probably critical to prolonging the effectiveness of HIV therapies in patients. In addition, CXCR(4) antagonists represent a novel class of drugs that could be used for the treatment of diseases other than HIV/AIDS. OBJECTIVE: An overview of the most pertinent chemical classes that modulate the CXCR(4) receptor, in addition to discussions of lead compound development. METHODS: The review primarily covers patents and patent application publications filed in the past 8 years. However, earlier patents are included to provide a historical context. RESULTS/CONCLUSION: The early bicyclam class proved untenable for HIV treatment due to cardiotoxicity and lack of desirable pharmacokinetic properties. Second generation bicyclam mimics have the benefit of oral bioavailability but have, as yet, not proven successful in the clinic. The peptidomimetic analogues discussed capitalize on known receptor binding site interactions, which could lead to the development of potent and orally available CXCR(4) antagonists.

Carboxylated, heteroaryl-substituted chalcones as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.

Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into the right range of lipophilicity. The chalcone alpha,beta-unsaturated ketone moiety seemed to be the pharmacophore required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic value for human asthma and other inflammatory disorders.

Discovery of novel heteroaryl-substituted chalcones as inhibitors of TNF-alpha-induced VCAM-1 expression.

Novel chalcone derivatives have been discovered as potent inhibitors of TNF-alpha-induced VCAM-1 expression. Thienyl or benzothienyl substitution at the meta-position of ring B helps boost potency while large substitution at the para-position on ring B is detrimental. Various substitutions are tolerated on ring A. A lipophilicity-potency relationship has been observed in several sub-series of compounds.

Computer-aided design of chiral ligands. Part III. A novel ligand for asymmetric allylation designed using computational techniques.

[reaction: see text] Computer-aided design protocols to identify new chiral ligands for reactions proceeding through well-defined transition states are outlined. Ligand families are discovered via computational screening of large structural databases such as the Cambridge Structural Database. Using this method, a novel cis-decalin ligand has been identified as a chiral auxiliary for the allylboration of aldehydes. Synthesis, resolution, and evaluation revealed that this new auxiliary provided the aldehyde facial approach upon which the design was predicated.