ABSTRACT
The potency and selectivity of a series of 5-hetero-2-iminohexahydroazepines were examined as inhibitors of the three human NOS isoforms. The effect of ring substitution of the 5-carbon for a heteroatom is presented. Potencies (IC(50)'s) for these inhibitors are in the low micromolar range for hi-NOS with some examples exhibiting a 500x selectivity versus hec-NOS.
Subject(s)
Azepines/pharmacology , Enzyme Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Azepines/chemical synthesis , Azepines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Nitric Oxide Synthase Type II , Structure-Activity RelationshipABSTRACT
An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Azepines/pharmacology , Enzyme Inhibitors/pharmacology , Imines/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Azepines/administration & dosage , Azepines/chemical synthesis , Azepines/pharmacokinetics , Biological Availability , Cell Line , Enzyme Induction/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Imines/administration & dosage , Imines/chemical synthesis , Imines/pharmacokinetics , Inflammation/blood , Inflammation/chemically induced , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/enzymology , Mice , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Rats , Rats, Inbred Lew , Recombinant Proteins/chemical synthesis , Recombinant Proteins/pharmacology , Structure-Activity RelationshipABSTRACT
A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 microM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Imines/chemical synthesis , Isoenzymes/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Piperidines/chemical synthesis , Animals , Cerebellum/enzymology , Endothelium, Vascular/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Imines/chemistry , Imines/pharmacology , Kinetics , Lipopolysaccharides/pharmacology , Male , Molecular Structure , Neurons/enzymology , Nitrates/blood , Nitrites/blood , Piperidines/chemistry , Piperidines/pharmacology , Rats , Rats, Inbred Lew , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A number of O- and N-alkylated derivatives of the antinociceptive, orally active, mu-opioid-selective truncated enkephalin analog L-2,6-dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide (2, SC-39566) were synthesized to explore the structure-activity relationships of the series. The parent molecule is quite forgiving of substitution on the tyrosyl phenolic moiety and on the alanyl nitrogen. The tyrosyl and (phenylpropyl)amide NH sites, however, appear to be critical to interactions with the receptor, for even modest changes at these sites cause great loss of binding potency.
Subject(s)
Analgesics, Opioid/pharmacology , Dipeptides/pharmacology , Enkephalins/pharmacology , Alkylation , Amino Acid Sequence , Analgesics, Opioid/metabolism , Animals , Dipeptides/metabolism , Enkephalins/metabolism , Male , Mice , Molecular Sequence Data , Rats , Rats, Sprague-Dawley , Receptors, Opioid/metabolism , Structure-Activity RelationshipABSTRACT
Rigid bifocal contact lens options continue to improve, with several new designs available in both the simultaneous and alternating vision categories. This paper reviews the selection of bifocal lens patients, describes basic lens designs, and provides guidelines for the successful fitting of rigid bifocal lenses.
Subject(s)
Contact Lenses , Refractive Errors/therapy , Humans , Patient Selection , Prosthesis Design , Prosthesis FittingABSTRACT
The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the delta opioid receptor and a 35-fold increase in potency at the mu receptor while substantial delta receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg. These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr1 with DMT.
Subject(s)
Analgesia , Analgesics/pharmacology , Enkephalins/pharmacology , Receptors, Opioid/physiology , Analgesics/chemical synthesis , Analgesics/metabolism , Animals , Brain/metabolism , Cell Membrane/metabolism , Electric Stimulation , Enkephalins/chemical synthesis , Enkephalins/metabolism , Male , Mice , Mice, Inbred ICR , Muscle Contraction/drug effects , Pain Measurement , Receptors, Opioid, delta , Receptors, Opioid, mu , Structure-Activity Relationship , Vas Deferens/drug effects , Vas Deferens/physiologyABSTRACT
1-(3-Chlorophenyl)-2-(4-hydroxphenyl)-1-methyl-2(2-pyridine)ethanol (8a) has been synthesized and found to be the major urinary metabolite following intraperitoneal administration of 1-(3-chlorophenyl)-1-methyl-2-phenyl-2-(2-pyridine)ethanol (1) to rats. This metabolite has a hypocholesteremic effect in rats similar to that of the parent drug.