ABSTRACT
Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.
Subject(s)
Receptors, LHRH/antagonists & inhibitors , Uracil/analogs & derivatives , Uracil/chemical synthesis , Uracil/pharmacology , Crystallography, X-Ray , Humans , Molecular Conformation , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Uracil/chemistryABSTRACT
A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.
Subject(s)
Pyridines/pharmacology , Receptors, LHRH/antagonists & inhibitors , Animals , Cells, Cultured , Humans , Pyridines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
Subject(s)
Appetite Depressants/chemical synthesis , Pyridazines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Thiophenes/chemical synthesis , Animals , Appetite Depressants/pharmacokinetics , Appetite Depressants/pharmacology , Biological Availability , Body Weight/drug effects , Brain/metabolism , Eating/drug effects , Half-Life , Male , Obesity/drug therapy , Permeability , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacologyABSTRACT
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Subject(s)
Chemistry, Pharmaceutical/methods , Chromones/chemical synthesis , Melanins/chemistry , Quinolones/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Pituitary Hormone/chemistry , Administration, Oral , Animals , Chromones/chemistry , Drug Design , Humans , Microsomes, Liver/metabolism , Models, Chemical , Quinolones/chemistry , Rats , Time FactorsABSTRACT
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.
Subject(s)
Amides , Pyrrolidines , Receptors, Somatostatin/antagonists & inhibitors , Urea , Amides/chemical synthesis , Amides/pharmacology , Animals , Drug Design , Molecular Conformation , Molecular Weight , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).
