ABSTRACT
1,4-Disubstituted imidazole inhibitors of Staphylococcus aureus and Escherichia coli enoyl acyl carrier protein reductase (FabI) have been identified. Crystal structure data shows the inhibitor 1 bound in the enzyme active site of E. coli FabI.
Subject(s)
Anti-Bacterial Agents/pharmacology , Imidazoles/pharmacology , Oxidoreductases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Escherichia coli Proteins , Fatty Acid Synthase, Type II , Imidazoles/chemical synthesis , Imidazoles/chemistry , Microbial Sensitivity Tests , Staphylococcus aureus/drug effectsABSTRACT
INTRODUCTION: Motor neuron diseases are always lethal. Other curable causes of neurologic disorders have to be sought. We report an example. EXEGESIS: A 72-year-old man presented a distal weakness and atrophy of the upper extremities. Electromyography showed thenar and hypothenar denervation, without fasciculation. Hypercalcemia led to the discovery of a primary hyperparathyroidism. Five months after parathyroid surgery, there was no worsening. CONCLUSION: Von Recklinghausen and Vical were the first to describe neuromuscular involvement in primary hyperparathyroidism. Faced with symptoms mimicking motor neuron diseases, calcium and phosphorus levels have to be measured because hyperparathyroidism can be cured and neurologic disorders disappear after surgery.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Hyperparathyroidism/diagnosis , Adenoma/diagnosis , Adenoma/surgery , Aged , Calcium/blood , Diagnosis, Differential , Electromyography , Humans , Hypercalcemia/diagnosis , Hypercalcemia/etiology , Hyperparathyroidism/blood , Hyperparathyroidism/etiology , Male , Parathyroid Neoplasms/diagnosis , Parathyroid Neoplasms/surgery , Parathyroidectomy , Phosphorus/bloodABSTRACT
The activity of a novel series of peptidomimetic hematoregulatory compounds, designed based on a pharmacophore model inferred from the structure activity relationships of a peptide SK&F 107647 (1), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The compounds may represent novel therapeutic agents in the area of hematoregulation.
Subject(s)
Cardiovascular Agents/chemical synthesis , Chemokines, CXC , Intercellular Signaling Peptides and Proteins , Oligopeptides/pharmacology , Amino Acids/chemistry , Animals , Candidiasis/drug therapy , Cardiovascular Agents/pharmacology , Cardiovascular Agents/therapeutic use , Cell Line , Chemokine CXCL1 , Chemotactic Factors/metabolism , Drug Design , Granulocyte Colony-Stimulating Factor/biosynthesis , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Growth Substances/metabolism , Macrophage Colony-Stimulating Factor/biosynthesis , Mice , Oligopeptides/chemistry , Receptors, Drug/chemistry , Receptors, Drug/drug effectsSubject(s)
Benzazepines/pharmacology , Pyridines/pharmacology , Receptors, Vitronectin/antagonists & inhibitors , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Biological Availability , Bone Resorption/prevention & control , Cell Adhesion/drug effects , Cell Line , Half-Life , Humans , Molecular Mimicry , Osteoclasts/drug effects , Osteoclasts/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Stereoisomerism , Tissue DistributionABSTRACT
Hematopoiesis is a lifelong cell renewal process regulated by a family of lineage specific hematopoietic growth factors. Several hematopoietic growth factors such as G-CSF, GM-CSF, and M-CSF have been clinically evaluated for enhancement of host defense in normal and immunocompromised patients and for the treatment of infectious diseases. This paper reports the structure-activity relationships of low molecular weight hematoregulatory peptides based on a nonapeptide (1, SK&F 107647). Like the macromolecular growth factors, these peptides modulate host defense. A molecular target for this class of compounds has not yet been identified. However, the structure-activity relationships established by this study implicate a very specific molecular recognition event that is pivotal for the biological activities of 1 and its analogues.
