Cyclic peptide inhibitors of lysine-specific demethylase 1 with improved potency identified by alanine scanning mutagenesis.

Lysine-specific demethylase 1 (LSD1) is a chromatin-remodeling enzyme that plays an important role in cancer. Over-expression of LSD1 decreases methylation at histone 3 lysine 4, and aberrantly silences tumor suppressor genes. Inhibitors of LSD1 have been designed as chemical probes and potential antitumor agents.

Synthesis and evaluation of novel cyclic Peptide inhibitors of lysine-specific demethylase 1.

Lysine specific demethylase 1 (LSD1) selectively removes methyl groups from mono- and dimethylated histone 3 lysine 4 (H3K4), resulting in gene silencing. LSD1 is overexpressed in many human cancers, resulting in aberrant silencing of tumor suppressor genes. Thus, LSD1 is a validated target for the discovery of antitumor agents.

Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain.

The conventional design of high affinity drugs targeted to a single molecule has not resulted in clinically useful therapies for pain relief. Recent reviews have suggested that newly designed analgesic drugs should incorporate multiple targets. The distributions of cholecystokinin (CCK) and CCK receptors in the central nervous system (CNS) overlap significantly with endogenous opioid systems and can be dually targeted.

3-[1-(4-Sulfamoylphenyl)-5-p-tolyl-1H-pyrazol-3-yl]propanoic acid and 3-[5-(4-bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl]propanoic acid-dichloromethane-diethyl ether-water (2/0.72/1/1).

The syntheses of 3-[1-(4-sulfamoylphenyl)-5-p-tolyl-1H-pyrazol-3-yl]propanoic acid, C(19)H(19)N(3)O(4)S, (I), and 3-[5-(4-bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl]propanoic acid-dichloromethane-diethyl ether-water (2/0.72/1/1), 2C(18)H(16)BrN(3)O(4)S.0.

3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]propionic acid and the corresponding methyl ester.

The synthesis of 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]propionic acid, C(19)H(17)ClN(2)O(3), (I), and its corresponding methyl ester, methyl 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]propionate, C(20)H(19)ClN(2)O(3), (II), is regiospecific. However, correct identification of the regioisomer formed by spectroscopic techniques is not trivial and single-crystal X-ray analysis provided the only means of unambiguous structure determination. Compound (I) crystallizes with Z' = 2.

1-(4-Methoxy-phen-yl)-3-phenyl-1H-pyrazol-5-amine.

The synthesis of the title compound, C(16)H(15)N(3)O, is regiospecific and single-crystal X-ray diffraction provides the only means of unambiguous structural analysis, with the benzene ring bonded to the imine C atom. The phenyl ring and the essentially planar (r.m.