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p-Nitrophenyl 3-diazopyruvate (DAPpNP) has been developed as a heterobifunctional cross-linking agent for synthesis of photoaffinity probes and photoactivatable cross-linking agents that are nucleophile specific. p-Nitrophenyl chloroglyoxylate is formed in high yield from oxalyl chloride and p-nitrophenol. Subsequent reaction with diazomethane produces… (More)
The central melanocortin system has been demonstrated to play an important role in regulating different aspects of energy homeostasis. Understanding the specific contributions of MC3 and MC4 receptors, however, requires specific agonists and antagonists for each of the predominant forms of brain melanocortin receptors, MC3-R and MC4-R. We report here the… (More)
Incorporation of substituted phenyl piperazine privileged structures into a known MC4 specific dipeptoid consensus sequence resulted in a series of potent (EC(50)=24 nM) and selective MC4-R agonists. We report the SAR of this series of compounds using in vitro cAMP functional assays in cells transfected with the MC4 or other melancortin receptors.
Derivatives of 1-(4-amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine were identified as potent and functionally active MCH-R1 antagonists. One compound with Ki = 2.3 nM demonstrated good oral bioavailability (32%) and in vivo efficacy in rats.
Diarylimidazolecarboxamides and diaryltriazolecarboxamides related to SR141716 were synthesized and tested for binding to the human CB(1) receptor. Suitably substituted imidazoles are comparably potent to the clinical candidate, whereas the analogous triazoles are less so due to the absence of an additional substituent on the azole ring.
During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral… (More)
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) is a significant source of disability in the HIV-infected population. Even with stringent adherence to anti-retroviral therapy, >50% of patients living with HIV-1 will develop HAND (Heaton et al., 2010). Because suppression of viral replication alone is not enough to stop HAND… (More)
There has been great interest in melanocortin (MC) receptors as targets for the design of novel therapeutics to treat disorders of body weight, such as obesity and cachexia. Both genetic and pharmacological evidence points toward central MC4 receptors as the principal target. Using highly selective peptide tools for the MC4 receptor, which have become… (More)
UNLABELLED Mixed lineage kinase 3 (MLK3) deficiency reduces macrophage-associated inflammation in a murine model of nonalcoholic steatohepatitis (NASH). However, the mechanistic links between MLK3 activation in hepatocytes and macrophage-driven inflammation in NASH are uncharted. Herein, we report that MLK3 mediates the release of (C-X-C motif) ligand 10… (More)
Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain… (More)