Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases
PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes.
By Ingallinella, Paolo; Peier, Andrea M.; Pocai, Alessandro; Di Marco, Annalise; Desai, Kunal; Zytko, Karolina; Qian, Ying; Du, Xiaobing; Cellucci, Antonella; Monteagudo, Edith; et al
From Bioorganic & Medicinal Chemistry (2012), 20(15), 4751-4759. Language: English, Database: CAPLUS, DOI:10.1016/j.bmc.2012.06.003
Neuromedin U (NMU) is an endogenous peptide, whose role in the regulation of feeding and energy homeostasis is well documented. Two NMU receptors have been identified: NMUR1, expressed primarily in the periphery, and NMUR2, expressed predominantly in the brain. We recently demonstrated that acute peripheral administration of NMU exerts potent but acute anorectic activity and can improve glucose homeostasis, with both actions mediated by NMUR1. Here, we describe the development of a metabolically stable analog of NMU, based on derivatization of the native peptide with high mol. wt. poly(ethylene) glycol (PEG) (‘PEGylation’). PEG size, site of attachment, and conjugation chem. were optimized, to yield an analog which displays robust and long-lasting anorectic activity and significant glucose-lowering activity in vivo. Studies in NMU receptor-deficient mice showed that PEG-NMU displays an expanded pharmacol. profile, with the ability to engage NMUR2 in addn. to NMUR1. In light of these data, PEGylated derivs. of NMU represent promising candidates for the treatment of obesity and diabetes.
Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
By Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; et al
From ACS Medicinal Chemistry Letters (2012), 3(4), 332-336. Language: English, Database: CAPLUS, DOI:10.1021/ml300017p
A new class of HCV NS3/4a protease inhibitors contg. a P2 to P4 macrocyclic constraint was designed using a mol. modeling-derived strategy. Building on the profile of previous clin. compds. and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clin. candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clin. relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.