ABSTRACT
A novel series of pyrrolopyrazole-based protein kinase C ß II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.
Subject(s)
Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , High-Throughput Screening Assays , Protein Kinase C/metabolism , Protein Kinase C beta , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
Subject(s)
Indenes/chemical synthesis , Morpholines/chemical synthesis , Pyrimidines/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Humans , In Vitro Techniques , Indenes/chemistry , Indenes/pharmacology , Inositol Phosphates/biosynthesis , Male , Morpholines/chemistry , Morpholines/pharmacology , Orchiectomy , Pituitary Gland/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism , Structure-Activity Relationship , Testis/drug effects , Testis/metabolism , Testosterone/antagonists & inhibitors , Testosterone/metabolismABSTRACT
A novel series of non-peptide derivatives 1, 14, and 15 that bind with high affinity to the human GnRH receptors is discussed. The discovery was made from screening our in-house libraries that contained the active structure 2 along with a trace amount of a second active structure 1 that was derived from an acid-induced rearrangement. From this structure type 1, a series of guanidine and non-guanidine containing analogues were prepared and tested as GnRH receptor antagonists. Compounds derived from this series bind to both human and rat GnRH receptors and antagonize GnRH-mediated increases in inositol phosphate production in cells containing recombinant human receptors. These compounds or their analogues may be useful as therapeutic agents for the treatment of hormone-dependent pathologies including prostate, breast and ovarian cancers.
Subject(s)
Guanidine/analogs & derivatives , Receptors, LHRH/antagonists & inhibitors , Animals , Drug Design , Guanidine/pharmacology , Hormone Antagonists/chemistry , Hormone Antagonists/pharmacology , Humans , Phosphoric Monoester Hydrolases/biosynthesis , Protein Binding , Rats , Receptors, LHRH/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of derivatives of mono- and diaminopyrimidines 1 potently displaced binding of a radiolabeled GnRH analogue to human and rat GnRH receptors. Analogues from these series competitively antagonized GnRH-stimulated increases in extracellular acidification in vitro and suppressed GnRH-mediated increases in circulating luteinizing hormone (LH) in castrated rats and testosterone in intact rats. These compounds or their analogues may be useful in treating sex hormone-dependent disease.
