ABSTRACT
Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.
Subject(s)
Azetidines/chemical synthesis , Quinolones/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Animals , Azetidines/chemistry , Azetidines/pharmacokinetics , Azetidines/pharmacology , Binding, Competitive , CHO Cells , Cricetinae , Humans , In Vitro Techniques , Macaca mulatta , Pituitary Gland/metabolism , Quinolones/chemistry , Quinolones/pharmacokinetics , Quinolones/pharmacology , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
The use of ultraviolet light (UVL) to study and document patterned injuries on human skin has opened a new frontier for law enforcement. This article discusses the photographic techniques involved in reflective and fluorescent UVL. Documentation of skin wounds via still photography and dynamic video photographic techniques, which utilize various methods of UV illumination, are covered. Techniques important for courtroom presentation of evidence gathered from lacerations, contusions, abrasions, and bite marks are presented through case studies and controlled experiments. Such injuries are common sequelae in the crimes of child abuse, rape, and assault.
