A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors.

A series of benzimidazole-based analogues of the potent MTP inhibitor BMS-201038 were discovered. Incorporation of an unsubstituted benzimidazole moiety in place of a piperidine group afforded potent inhibitors of MTP in vitro which were weakly active in vivo. Appropriate substitution on the benzimidazole ring, especially with small alkyl groups, led to dramatic increases in potency, both in a cellular assay of apoB secretion and especially in animal models of cholesterol lowering. The most potent in this series, 3g (BMS-212122), was significantly more potent than BMS-201038 in reducing plasma lipids (cholesterol, VLDL/LDL, TG) in both hamsters and cynomolgus monkeys.

Herpes zoster and postherpetic neuralgia in the elderly.

This article describes herpes zoster (HZ), its cause, diagnosis, treatment, and associated complications. Postherpetic neuralgia (PHN), the most common complication of HZ, is the primary focus of the discussion. PHN is defined broadly as chronic pain that persists after the characteristic vesicular rash of HZ has resolved.

N-formyl hydroxylamine containing dipeptides: generation of a new class of vasopeptidase inhibitors.

Four primary zinc-binding pharmacophores (thiols, carboxylates, phosphorus acids, and hydroxamates) have been utilized in generating inhibitors of zinc metalloproteases such as ACE, NEP, the MMPs, and ECE. Although compounds which inhibit the activity of both ACE and NEP (vasopeptidase inhibitors, VPIs) have been reported which incorporate a thiol, carboxylate, or phosphorus acid pharmacophore, the generation of hydroxamate based vasopeptidase inhibitors has remained elusive. Herein we report the first potent vasopeptidase inhibitors which were generated from the incorporation of conformationally restricted dipeptide mimetics to an N-formyl hydroxylamine zinc-binding group. Compounds such as 13c and 13d are among the most potent in this series, exhibiting in vitro activity comparable to other classes of inhibitors.

Vasopeptidase inhibitors: incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides.

A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.

An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.

Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Dual metalloprotease inhibitors. 6. Incorporation of bicyclic and substituted monocyclic azepinones as dipeptide surrogates in angiotensin-converting enzyme/neutral endopeptidase inhibitors.

A series of substituted monocyclic and bicyclic azepinones were incorporated as dipeptide surrogates in mercaptoacetyl dipeptides with the desire to generate a single compound which would potently inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Many of these compounds displayed excellent potency against both enzymes. Two of the most potent compounds, monocyclic azepinone 2n and bicyclic azepinone 3q, demonstrated a high level of activity versus ACE and NEP both in vitro and in vivo.

Influence of tryptophan residues on melittin's hemolytic activity.

Earlier studies of melittin have shown that the Trp residue at position 19 is significantly involved in its hemolytic activity. Tryptophan residues have also been reported to play a specific and important role in a number of other biological interactions. In the present study, we investigated what effect the introduction of a second Trp residue would have on melittin's hemolytic activity. This was accomplished through the synthesis and analysis of a complete set of 25 single-position, synthetic Trp substitution analogs. Significant increases in activity were observed upon substituting Trp at a single residue at either extreme of melittin's two alpha-helices, or in its 'hinge' region. Decreases in activity were found upon replacing any of melittin's Leu residues with Trp. The changes in activity of all of the analogs relative to melittin were found to be correlated to their behavior during RP-HPLC, as was their variation in percent helicity in the presence of liposomes.

The effects of elastic tights on the post-exercise response.

It has previously been demonstrated that graduated compression stockings will affect the post-exercise venous lactate profile. To determine the effects of elastic tights on venous lactate levels and the post-exercise response, eight males completed three exercise bouts on a motor driven treadmill. Each subject ran on the treadmill for up to three minutes at 110% of his VO2max. The conditions for the three exercise bouts were: elastic tights worn during exercise and recovery, elastic tights worn only during exercise, and no elastic tights worn during exercise or recovery. Oxygen consumption, heart rates and venous blood samples, for lactate and hematocrit determination, were obtained at rest and at 5, 15 and 30 min post-exercise. Analysis revealed no significant differences (p greater than 0.05) in any of the above variables between the three trials at any of the measurement times. These results indicate that the use of elastic tights will not significantly affect the post-exercise response or circulating lactate levels.

1-Acyltriazoles as antiinflammatory agents.

Certain 1-acyl-3-phenyl-5-alkyltriazoles were synthesized and evaluated for antiinflammatory activity using the mouse active Arthus (MAA) reaction as the test system. Modification of the acyl group, 4-phenyl substituent, and alkyl group led to the selection of the most active member of this series, 1-acetyl-3-(4-chlorophenyl)-5-methyl-1,2,4-triazole (3c), for further evaluation as a novel nonacidic antiinflammatory agent.