Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.

Substituted piperidines--highly potent renin inhibitors due to induced fit adaptation of the active site.

The identification, synthesis and activity of a novel class of piperidine renin inhibitors is presented. The most active compounds show activities in the picomolar range and are among the most potent renin inhibitors ever identified.

Piperidine-renin inhibitors compounds with improved physicochemical properties.

Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic attachments show improved physical properties (lower lipophilicity, improved solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517 and a log D(pH 7.4) of 1.9 displays potent and long lasting blood pressure lowering effects after oral administration to sodium depleted conscious marmosets.

Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?

BACKGROUND: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. RESULTS: High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. CONCLUSIONS: The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.

Lymphocytic colitis: clinical presentation and long term course.

BACKGROUND: Lymphocytic colitis is characterised by chronic watery diarrhoea with normal endoscopic or radiological findings and microscopic evidence of pronounced infiltration of the colonic mucosa with lymphocytes. AIM: To investigate the long term clinical and histological evolution of the disease in a large group of patients with well characterised lymphocytic colitis. METHODS: Between 1986 and 1995 the histological diagnosis of lymphocytic colitis was obtained in 35 patients; 27 of these agreed to a follow up examination. All clinical, endoscopic, and histopathological records were reviewed at that time and the patients had a second endoscopic examination with follow up biopsies. RESULTS: The patients initially presented with the typical findings of lymphocytic colitis. After a mean (SD) follow up of 37.8 (27.5) months, diarrhoea subsided in 25 (93%) and histological normalisation was observed in 22 (82%) of the 27 patients. Progression from lymphocytic colitis to collagenous colitis was not observed. CONCLUSIONS: Lymphocytic colitis is characterised by a benign course with resolution of diarrhoea and normalisation of histology in over 80% of patients within 38 months. Considering the benign course of the disease, the potential benefit of any drug treatment should be carefully weighed against its potential side effects.

[Colonic preparation with sodium phosphate. Prospective, randomized, placebo-controlled double blind study with various antiemetics]. / Dickdarmvorbereitung mit Natriumphosphat, Prospektive, randomisierte, plazebokontrollierte Doppelblindstudie mit verschiedenen Antiemetika.

UNLABELLED: The well established bowel cleansing method using a polyethylene glycol-based solution (Fordtran) is limited by the necessity of large volume intake, which proves difficult for many patients. Therefore, a new method using small volumes (2 x 90 ml) of oral sodium phosphate is employed more and more frequently. Its only disadvantage is the occurrence of considerable nausea or occasional vomiting in about 25% of patients. To ascertain whether nausea could be reduced, 426 patients were given an antiemetic (ondansetron, metoclopramide, cisapride) or placebo on a randomized, double-blind basis, one hour before sodium phosphate intake. RESULTS: sodium phosphate was well tolerated in 69.2% of the patients on placebo, 73.6% on cisapride, 76.5% on metoclopramide and 80.4% on ondansetron. Taking all four groups together, male patients exhibited much better tolerance (86.1%) than females (66.1%). Severe nausea and/or emesis was noted in 22.4% of patients on placebo, 21.7% on cisapride, 17% on metoclopramide and 14% on ondansetron. In over 90% of patients colon cleansing was rated as good to very good. This was largely independent of the severity of nausea. 129 patients who had undergone former polyethylene glycol-based lavage judged sodium phosphate to be more tolerable and easier to complete. Considering known contraindications (symptomatic congestive heart failure and/or renal failure), no serious adverse event was noted in any of the 426 patients investigated. In accordance with several recent studies, we consider sodium phosphate solution at present the procedure of choice for colon cleansing. Compared to Fordtran, patient acceptance is far better and cleansing quality superior. Routine antiemetic comedication for reducing possible nausea/vomiting is not worthwhile. On the other hand, this study confirms our former impression of enhanced colon cleansing after administration of an additional mild laxative before sodium phosphate, without interfering with patient acceptance.

[Vanner solution--a novel low-volume, patient-friendly colon preparation]. / Vanner-Lösung--neuartige kleinvolumige, patientenfreundliche Dickdarmvorbereitung.

Many patients have great difficulty drinking the large volume of Fordtran solution, which has become the standard preparation for colonoscopy since 1980. We have evaluated a new method, using two 90-ml small-volume doses of oral sodium phosphate as osmotic laxative in 210 patients who had all had a previous colonoscopy preparation with Fordtran solution. Sodium phosphate was preferred by 81% of the patients, and it produced a better quality of cleansing at much lower cost. Oral sodium phosphate appears to be the preparation of choice for colonoscopy. Contraindications are congestive heart failure or renal insufficiency.

[Colorectal carcinoma: screening and prevention]. / Kolon-Rektum-Karzinom: Screening und Prävention.

Efficient screening for colorectal carcinoma is urgently needed because of its high incidence and its notoriously poor postoperative prognosis. At present only earlier diagnosis at a better prognostic stage will improve 5-year survival rates. Currently available means of detecting colorectal neoplasia and special risk populations are presented. Gastroenterological and oncological groups in the USA and Europe have put forward recommendations for 5-yearly flexible sigmoidoscopy for each person aged 45 years or over, a desirable yet unrealistic demand in view of limited financial and manpower resources. This paper therefore attempts to identify the various risk groups and to attribute to them individually an appropriate screening policy. For the normal general population with no specific risk factors in its personal or family history, yearly fecal occult blood testing remains the cheapest and most widely available minimal program, although current evidence indicates that this test misses over half of colonic malignancies (and even more benign adenomas). Special risk groups must be included in colonoscopy surveillance programs. Choice of the screening method for a given patient is usually the responsibility of the primary physician. The main hope for improving the present unsatisfactory situation stems from recent spectacular advances in molecular biology, which has discovered a number of tumor suppressor genes and oncogenes. If attempts at broad clinical identification of these chromosomal factors are successful, better determination of the risk of any given individual patient, and hence improved assignment of the adequate screening method, will be possible.

[Collagenous colitis]. / Die Kollagenkolitis.

The features of collagenous colitis are briefly summarized on the basis of 24 own patients and a review of the literature. Collagenous colitis is a rare diarrheal disease first described in 1976. The hallmark of this syndrome consists in a thickened layer of subepithelial collagen in the entire colon. Clinically patients present with longstanding, watery diarrhea. Laboratory tests, radiology and colonoscopy are all normal. Therefore the diagnosis is only established, if an alert colonoscopist takes biopsies out of an endoscopically normal appearing mucosa. There is no specific treatment, but patients usually respond to symptomatic therapy with antidiarrheal drugs. Microscopic colitis may represent an early stage of collagenous colitis.

[Side effects of non-steroidal antirheumatic agents in the lower gastrointestinal tract]. / Die Nebenwirkungen nicht-steroidaler Antirheumatika im unteren Gastrointestinaltrakt.

Peptic gastroduodenal lesions due to nonsteroidal antiinflammatory drugs (NSAID) are well known, but not the adverse effects of these preparations in the lower GI tract. The cases of 5 patients with NSAID-induced colitis are described and the pertinent literature is reviewed, which reveals a wide spectrum of alterations ranging from mild non-specific colitis to acute bleeding or perforation. The most important key to correct diagnosis is a careful drug history, and treatment is to discontinue the NSAID.

Gastric ulcer: a double blind comparison of 800 mcg misoprostol versus 300 mg ranitidine.

Seventy-nine patients with endoscopically confirmed gastric ulcers received either ranitidine (37 patients) or misoprostol (42 patients) in a randomized double-blind manner. Fifty-six percent of the patients treated with ranitidine, and 38% of those treated with misoprostol presented with endoscopically healed ulcers after four weeks of treatment. After eight weeks complete healing had occurred in 86% of the patients receiving ranitidine, and 74% of those on misoprostol. These differences were not statistically significant. In smokers, ranitidine was superior to misoprostol, leading to a higher healing rate at four weeks (73% versus 20%). Thus there was no evidence that in patients with gastric ulcer misoprostol overcomes the negative effect of cigarette smoking.

[Collagenous sprue and ulcerative jejuno-ileitis in a patient with gluten-induced enteropathy]. / Kollagensprue und ulzerierende Jejunoileitis bei einem Patienten mit gluteninduzierter Enteropathie.

In a 60-year-old patient with adult celiac disease complete clinical remission was achieved with a glutenfree diet, but symptoms of sprue subsequently recurred despite rigid adherence to dietary restrictions. Further investigations revealed simultaneous occurrence of two severe complications of celiac disease: collagenous sprue and ulcerative jejunoileitis. The patient died after a 2 1/2 year course of refractory, severe, relentlessly progressive malabsorption. In the light of the literature and this observation it is postulated that in every case of primary or secondary refractory celiac disease complications must be sought: to diagnose collagenous sprue, aspiration biopsy from the proximal jejunum, and possibly also from the terminal ileum, may be more efficient than simple endoscopic biopsy from the descending duodenum. If the diagnosis of collagenous sprue can be established, therapy with steroids should be attempted. The diagnosis of ulcerative jejunoileitis is usually missed by radiology and requires exploratory laparotomy.

[Ranitidine therapy of duodenal ulcer: comparison of once-a-day and twice-a-day administration. A Swiss multicenter double-blind study]. / Ranitidintherapie des Ulcus duodeni: Vergleich der zweimaligen und der einmaligen Applikation. Eine multizentrische Schweizer Doppeltblindstudie.

In a Swiss multicenter double-blind trial ranitidine was given in doses of 300 mg nocte and 150 mg b.d. for the treatment of duodenal ulcer. Ninety-seven patients with endoscopically proven ulcer were treated for four, and in cases of non-healing for eight, weeks. Cumulative healing rates with 300 mg and 2 X 150 mg were 77% and 78% after four weeks and 90% and 94% after eight weeks respectively. 60 and 65% of the patients were asymptomatic after four weeks. Smoking did not adversely affect healing. Thus, ranitidine in a dose of 300 mg nocte is as effective as ranitidine in a dose of 150 mg b.d. in the treatment of duodenal ulcer.

[Misoprostol and cimetidine in the treatment of duodenal ulcer. A multicenter Swiss double-blind study]. / Misoprostol und Cimetidin bei der Behandlung des Ulcus duodeni. Eine multizentrische Schweizer Doppeltblindstudie.

The efficacy and tolerance of misoprostol a synthetic prostaglandin E1 analogue-and of cimetidine were evaluated in the treatment of duodenal ulcer following a double blind multicenter design. A group of Swiss gastroenterologists recruited 119 patients with endoscopically proven acute duodenal ulcer. They were enrolled and treated according to a uniform protocol either with misoprostol 4 X 50 micrograms daily, with misoprostol 4 X 200 micrograms daily or with cimetidine 4 X 300 mg daily. Patients who were healed after 4 or 8 weeks were followed during 6 months. Cumulative healing rates at 4 weeks in groups receiving misoprostol 200 micrograms, misoprostol 800 micrograms or cimetidine 1200 mg daily were 42%, 58% and 71% respectively. Patients treated with cimetidine showed a more rapid improvement of symptoms than patients treated with misoprostol. Symptomatic recurrences after ulcer healing occurred in almost 40% of the patients within 6 months, irrespective of the type of acute ulcer treatment. Risk factors for slowed healing and increased rate of recurrence were evaluated in the present study, and the results were compared with the results of two previous trials performed according to a similar protocol. Smoking appeared to slow healing and to favor relapses. Moderate consumption of alcohol appeared to decrease the relapse rate. In the present trial, ulcer size was associated with ulcer pain but not with ulcer healing.

[Methods for the early detection of colonic polyps and colonic cancers]. / Methoden zur Früherfassung von Kolonpolypen und Kolonkarzinomen.

The dramatically rising incidence of colorectal cancer and the fact that survival rates can only be improved by earlier diagnosis call for increased efforts aimed at early detection of colonic neoplasias. Present diagnostic methods--occult blood testing, digital exam, rigid and flexible sigmoidoscopy, double contrast barium enema and colonoscopy--are analyzed with regard to diagnostic yield, time requirement and patient acceptability. Flexible sigmoidoscopy has proved to be of high diagnostic value, to take relatively little time and to cause only minimal patient discomfort. It will therefore gradually replace rigid sigmoidoscopy. Various populations at risk for colorectal cancer are outlined and appropriate diagnostic screening methods are described. Finally, a plan for monitoring of the normal risk population is proposed.

[Collagen colitis. A new disease picture or merely a histological abnormality?]. / Die "Kollagenkolitis". Ein neues Krankheitsbild oder blosse histologische Abnormität?

"Collagenous colitis" has been recently defined as a new entity characterized by protracted diarrhoea, associated with subepithelial broadening of the collagen layer. A report is presented on two patients fulfilling the above criteria. Based on a critical analysis of these two cases and on prospective study of biopsies in 50 consecutive coloscopies it is concluded that a causal relationship between the enlarged collagen layer and the diarrhoea cannot be unequivocally established and hence "collagenous colitis" should not yet be considered a new entity.