Jeffrey Daniel Cohen

Potent nonsteroidal progesterone receptor agonists: Synthesis and SAR study of 6-aryl benzoxazines

Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists, the 6-aryl benzoxazines were potent PR agonists. Compounds 4e, 5b, and 6a with the 2,4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonists in the series with sub-nanomolar activities (EC(50) 0.20-0.35nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED(50) of 1.5mg/kg (vs 5.62mg/kg for P4).

New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles

A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this communication, the synthesis and structure-activity relationships (SARs) of various 3,3-substituents are discussed where it is clear that small alkyl and spiroalkyl groups are required to achieve better PR antagonist activity.

Synthesis and progesterone receptor antagonist activities of 6-aryl benzimidazolones and benzothiazolones.

Novel 6-aryl benzimidazolones and benzothiazolones were prepared and examined as bioisosteres of the recently reported 6-aryl dihydroquinolines (1) for progesterone receptor (PR) antagonist activities. PR antagonist activities increased when compounds 9c-f possessed a more lipophilic group at position-1 and pendent aryl moiety para to NH moiety. Furthermore, conversion of carbonyl moiety of 9e,f to the thio-carbonyl led to benzoimidazolethiones 15a,b with significantly improved potency and binding affinity.

Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

Hexadecyloxypropyl-cidofovir (CMX001) suppresses JC virus replication in human fetal brain SVG cell cultures.

ABSTRACT JC virus (JCV) is a polyomavirus that infects human oligodendrocytes, leading to development of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease occurring in immunocompromised individuals. Currently there are no effective therapies for the treatment of PML that result in clearance of JCV from the brain. Cidofovir (CDV) is an acyclic nucleoside phosphonate that inhibits DNA polymerases and has been used for the treatment of PML. However, CDV demonstrated little efficacy as a treatment for PML and causes substantial side effects to patients. To improve efficacy and reduce the toxicity of CDV, a lipid-ester derivative, CMX001, was generated by Chimerix and is currently in multicenter phase II clinical trials for the prevention or control of cytomegalovirus infection in hematopoietic stem cell transplant recipients and of BK virus in the urine of stem cell or renal allograft recipients. CMX001 caused minimal cytotoxic effects in human fetal brain SVG cells when used at concentrations between 0.01 μM and 0.1 μM. CMX001 resulted in a dose-dependent decrease in the number of JCV-infected cells during initial infection and nearly eliminated JCV-infected cells during an established infection. In addition, CMX001 treatment resulted in a 60% reduction in JCV DNA copy number during initial infection, which suggests that suppression of JCV infection by CMX001 is likely due to inhibition of virus DNA replication. This study demonstrates that CMX001 suppresses JCV infection at concentrations that have limited toxicity to human brain cells, indicating its potential use to limit JCV replication in infected patients.

Novel 5-aryl-1,3-dihydro-indole-2-thiones: potent, orally active progesterone receptor agonists

During the course of our studies on 3,3-disubstituted-5-aryloxindoles derived progesterone receptor (PR) antagonists we discovered that changing the amide funtionality to a thio-amide resulted in compounds displaying potent PR agonist activity. In this communication, the synthesis, structure activity relationships (SAR) and in vivo activity of various 5-arylthio-oxindoles will be discussed.

Inhibition of human rhinovirus 3C protease by homophthalimides

Abstract Homophthalimides 2a and 3a were found to be inhibitors of Rhinovirus 3C protease through a blind screening effort. SAR studies resulted in compound 3g, which exhibited improved enzyme inhibition, in addition to whole cell antiviral activity. Molecular modeling studies suggest a preferred enzyme/inhibitor interaction, and LC/MS experiments confirmed tight/covalent binding of 3g to the enzyme.