3,5-Disubstituted quinolines as novel c-Jun N-terminal kinase inhibitors

The structure-based design and synthesis of a novel series of c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38 is reported. The unique structure of 3,5-disubstituted quinolines (2) was developed from the previously reported 4-(2,7-phenanthrolin-9-yl)phenol (1). The X-ray crystal structure of 16a in JNK3 reveals an unexpected binding mode for this new scaffold with protein.     

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone, (HDMP) to prevent ‘trafficking’ of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the ‘blood brain barrier (BBB)’. Three men with newly diagnosed PCNSL, ages 62, 76 and 78 y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin’s lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70 y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.     

Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists

A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.     

Small molecule tertiary amines as agonists of the nuclear hormone receptor Rev-erbα

The structure-activity relationship study of a small molecule Rev-erbα agonist is reported. The potency and efficacy of the agonists in a cell-based assay were optimized as compared to the initial lead. Modest mouse pharmacokinetics coupled with an improved in vitro profile make 12e a suitable in vivo probe to interrogate the functions of Rev-erbα in animal models of disease.     

Imidazopyridines as selective CYP3A4 inhibitors

Cytochrome P450s are the major family of enzymes responsible for the oxidative metabolism of pharmaceuticals and xenobiotics. CYP3A4 and CYP3A5 have been shown to have overlapping substrate and inhibitor profiles and their inhibition has been demonstrated to be involved in numerous pharmacokinetic drug-drug interactions. Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity.     

N-aryl-prolyl-dipeptides as potent antagonists of VLA-4

The design, synthesis, and biological evaluation of N-arylprolyl-dipeptide derivatives as small molecule VLA-4 antagonists is described. Potency against VLA-4 and alpha(4)beta(7) and rat pharmacokinetic evaluation revealed some advantages over the related N-(arylsulfonyl)-prolyl-dipeptide analogues.     

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.     

Synthesis and SAR of 2-phenoxypyridines as novel c-Jun N-terminal kinase inhibitors

The design and synthesis of a novel series of c-jun N-terminal kinase (JNK3) inhibitors is described. The development and optimization of the 2-phenoxypyridine series was carried out from an earlier pyrimidine series of JNK1 inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered.     

Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models

Background

Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine.

Methods

We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope.

Results

We applied our method to ID₅₀ neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF)?>?6), a subset of which were experimentally confirmed using site-directed mutagenesis.

Conclusions

Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth.