The In Vivo Activity of SCH 48461

The effect of SCH 48461 in cholesterol-fed rhesus monkeys is summarized, along with control animals, in Figure 3. The total serum cholesterol level in the control animals steadily increased over a period of 3 weeks compared with the monkeys dosed with SCH 48461 at 1 mgkg_ 1 over the course of the same period. The serum cholesterol levels did not show any significant change in the SCH 48461 group, and remained at the baseline. At the end of 3 weeks the control Figure 3 Effect of SCH 48461 in...

Raloxifene and Bone

Beall and coworkers162 published the first report of the actions of a nonsteroidal antiestrogen clomiphene on bone maintenance in ovariectomized rats. Unfortunately, these studies were flawed, as clomiphene is a mixture of the antiestrogenic E isomer and the estrogenic Z isomer. Clearly, it was possible that one isomer produced a dominant estrogenic effect in bone but the other isomer produced a dominant antiestrogenic effect in uterus and breast. The uncertainty was clarified with the finding...

Nonsteroidal Antiestrogens

Tamoxifen was not the first antiestrogen but the value of the drug slowly increased as the fashions in research changed. During the late 1950s and throughout the 1960s there was a focus on the development of new contraceptives in the wake of the success of oral contraceptives. These medicines did not treat a disease but altered lifestyle so there was huge potential for widespread use. But the application of antiestrogens as contraceptives failed and the compounds were drugs looking for a...

Relationship between Mechanism of Action and Toxicology

Toxicological animal studies have been published on ALN, clodronate, etidronate, incadronate, pamidronate, and tiludronate. When bisphosphonates are administered subcutaneously, local toxicity can occur, with local inflammation and necrosis. This is especially the case for the N-BPs. Clinical evidence of upper gastrointestinal irritation is observed in some patients.115,116 The risk of this problem is reduced through dosing instructions designed to avoid both esophageal tablet retention and...

References

Lancet 1896, 2, 104-107. 2. Boyd, S. Br. Med. J. 1900, ii, 1161-1167. 3. Jensen, E. V Jacobson, H. I. Rec. Prog. Hormone Res. 1962, 18, 387-414. 4. Gorski, J. Toft, D. Shyamala, G. Smith, D. Notides, A. Rec. Prog. Hormone Res. 1968, 24, 45-80. 5 . McGuire, W L. Carbone, P P. Volmer, E . P. In Oestrogen Receptor in Human Breast Cancer McGuire, W L. , Carbone, P. P. , Volmer, E . P , Eds . Raven Press New York, 1975, pp 6-19. 6. Lerner, L. J. Holthaus, J. F Thompson, C. R....

Discovery of the Prototype Azetidinone Cholesterol Absorption Inhibitor

The discovery program that led to ezetimibe began as a traditional drug discovery program to discover novel acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitors.14 Although ACATwas known to be involved in a variety of cholesterol trafficking events including cholesterol absorption in rodents, the relevance of ACAT in nonrodent species was still unclear at the time this program began. Nonetheless, a variety of structural classes were known to be potent ACAT inhibitors in vitro and to be...

Structure Activity Relationship on the Azetidinone Nucleus

Starting from the initial discovery of 14 by Burnett et al., follow-up studies focused on establishing the SAR profile around the azetidinone nucleus.20 While important in any medicinal chemistry effort, this was an especially critical early step in this program since it established that the observed in vivo activity followed predictable SARs despite the potential complications associated with use of an in vivo rather than an in vitro model. Among other things, these early studies confirmed the...

Evolution of Antiestrogens to Raloxifene

The scientific knowledge that Eli Lilly and Company utilized to develop raloxifene in the 1990s was based on (1) earlier studies performed in the 1960s to develop novel contraceptives100,101 and (2) knowledge of the structure-function relationships of antiestrogens in the 1970s.102 While many of the compounds failed as contraceptives, they ultimately evolved into antiestrogens and subsequently SERMs with multiple applications in medicine.67,103 The path leading to SERM development began with...

Lasofoxifene

Lasofoxifene Figure 10 is a novel nonsteroidal SERM that is in clinical trials for the prevention and treatment of osteoporosis in postmenopausal women.195 It is a diaryltetrahydronaphthalene derivative referred to as CP336156. The structure of CP336156 is reminiscent of nafoxidine Figure 3 if it were to be demethylated in vivo. There are two diastereometric salts. CP336156 is the L enantiomer that has 20 times the binding affinity of the D enantiomer. Studies Figure 10 Bazedoxifene,...

Urge Urinary Incontinence and Overactive Bladder

Interestingly, the impetus for studying duloxetine was for discovering a treatment of urinary urge incontinence and overactive bladder. Insertion of EMG electrodes into the rhabdosphincter was a compulsion instilled in me during my dissertation studies to obtain as much data as practical from every experiment conducted. Even after seeing pronounced effects on the rhabdosphincter, I was still more impressed with the effects on the bladder and anticipated clinical benefits for urge incontinence...

Figure 5 ac PKPD model for resistance development for HIV protease inhibitors d idealized PKPD profile with high

Model Alzheimer

Sufficient resistance to overcome all drug concentrations encountered in a dosing cycle are produced, the drug loses its antiviral effect, and viral load rebounds to pretherapy levels Figure 5a-c . This PK PD resistance model suggested that resistance could be delayed or prevented if a the drug was substantially more potent i.e., much lower EC50 , and or b the drug maintained higher plasma concentrations particularly trough concentrations Figure 5d . Both of these goals were realized with the...

The First Step The Discovery of Adrafinil

In the early 1970s, the Research Department of Laboratoire Louis Lafon, a small family-owned pharmaceutical company located in Maisons-Alfort, a suburb of Paris, had focused its research activities in three areas 1 cardiovascular 2 antispasmodics and 3 nonsteroidal anti-inflammatory drugs NSAIDs analgesics. In this last field, an empirical test battery was implemented, using the best-characterized in vivo pharmacological methods generally in use at that time some of which are still used . These...

The Multiple Actions of Carvedilol Antioxidant Properties

However, following detailed medical and commercial analyses, the company decided not to aggressively pursue the indications of angina and hypertension for a number of reasons 1 there was little medical need for another drug to treat these disorders, 2 there were, at the time, no known properties of carvedilol to differentiate the drug from others in the class, 3 generic beta blockers were already available and in wide use, and 4 due to the high promotional expenditure that would be required to...

Immunological Properties of Glatiramer Acetate

Several immunological properties of GA are thought to contribute to the effects of GA. 8.14.4.1.1 Binding to major histocompatibility complex molecules GA exhibits a very rapid, high, and efficient binding to many different MHC class II haplotypes on living murine and human antigen-presenting cells APCs . GA was also shown to interact with purified human leukocyte antigen HLA -DR molecules - DR1, DR2, and DR4 - with high affinity.45 As a result of its high and efficient binding to MHC class II...

Concerns about Tamoxifen

During the 1990s several important aspects of the pharmacology of tamoxifen emerged that had an impact on the clinical use of the drug. Each aspect was to create severe problems for developing the medicine from a treatment to a chemopreventive. Nevertheless, the rigorous evaluation of tamoxifen proved to be invaluable to understand the actions of the drug fully so that a solid clinical data base could be used to introduce improved medicines. There were three principal areas of concern. First,...

Tamoxifen

V C Jordan, Fox Chase Cancer Center, Philadelphia, PA, USA 2007 Elsevier Ltd. All Rights Reserved. 8.08.1 Background and Introduction 83 8.08.2 Nonsteroidal Antiestrogens 83 8.08.3 The Discovery of ICI46,474 86 8.08.4 Studies Published by Scientists at ICI Pharmaceuticals Division 86 8.08.5 Patenting Problems 88 8.08.6 A Conversation between the Laboratory and the Clinic 89 8.08.7 Twenty-First Century View of Tamoxifen as a Treatment for Breast Cancer 91 8.08.8 Concerns about Tamoxifen 91...

Lower Urinary Tract Function and Dysfunction

Micturition Control Circuit

The function of the lower urinary tract is to store and periodically release urine.1 The lower urinary tract is composed primarily of smooth muscle that forms a reservoir the urinary bladder and an outlet the urethra , which has a 'valve' -the urethral rhabdosphincter - that is composed of striated muscle. Regulation and coordination of urine storage and release i.e., micturition is accomplished by a series of spinal and spinobulbospinal reflexes, respectively Figure 1 . These reflexes can be...

Conclusion

Adefovir dipivoxil Hepsera is an excellent example of a prodrug that can overcome the oral delivery problem associated with poor permeation across the intestinal mucosa. Since its launch in 2002, Hepsera has become an important agent for the treatment of hepatitis B patients with evidence of active viral replication. A safety profile similar to placebo has been observed for Hepsera, which allows it to be prescribed as an effective drug for chronic treatment of hepatitis B. 1. World Health...

Demonstration of a Structure Toxicity Relationship A Strategy for Lead Progression

Fairly early on in our exploratory project we had identified one particularly interesting compound that demonstrated very good in vitro potency and oral in vivo efficacy comparable to DuP-721, and was found to have similar PK properties in the rat. This was the indanone oxazolidinone -U-82965 5, PNU-82965 ,24,25 one of two cyclic ketones we had targeted in order to explore the consequence of restricting the rotational conformers of the DuP-721 methyl ketone, via constraint in a five- or...

Immunological Effects of Glatiramer Acetate in Multiple Sclerosis Patients 814421 Antibody response

Evaluation of the immunological responses to GA in MS patients revealed that all patients treated with GA developed anti-GA antibodies, whereas placebo-treated patients were negative.74 The antibody level peaked at 3 months after initiation of treatment and reached a level of 8-20-fold above baseline. It decreased at 6 months and remained low. The anti-GA-reactive antibodies were of immunoglobulin G IgG type, with IgG1 levels two- to threefold higher than those of IgG2 at all time points...

Biographies

Robert R Ruffolo is currently President of Research amp Development for Wyeth Pharmaceuticals, and corporate Senior Vice President of Wyeth. He joined Wyeth in 2000 as Executive Vice President, responsible for Pharmaceutical Research and Development. Prior to joining Wyeth, Dr Ruffolo spent 17 years at SmithKline Beecham Pharmaceuticals where he was Senior Vice President and Director of Biological Sciences, Worldwide. Before joining SmithKline Beecham, Dr Ruffolo spent 6 years at Lilly Research...

The Discovery of Posaconazole

Medicinal Chemistry Health And Healthy

Posaconazole15 21 is a novel triazole that has broad-spectrum antifungal activity against Aspergillus spp., Cryptococcus spp., Histoplasma spp., and a variety of other pathogens. In the clinic, posaconazole has been found to be well tolerated, with common side effects being gastrointestinal in origin. Life-threatening opportunistic fungal infections occur in AIDS patients, and also in patients undergoing chemotherapy for cancer, or those who have undergone organ transplants. The older...

The Design of Ezetimibe

Based on the activity of 9, the phenols 10, 11, 12, 13, 14, and 15 were synthesized, and their in vivo activities determined. The results are summarized in Figure 4. Based on the structure-activity relationship as described in Figure 2 and also on the biological activities of the possible metabolites as described in Figure 4, several new analogs were synthesized. Ezetimibe was found to be the most potent among all the analogs synthesized in inhibiting the absorption of cholesterol. The...

G13 Case

Figure 1 A HO, R Pr, isoproterenol A MeSO2NH, R iPr soterenol A HOCH2, R tBu, albuterol. reported significant lowering of blood pressure in hypertensives by propranolol, opposite to what was predicted because of its predominant effect on cardiac function rather than peripheral vasculature. By following rather than leading with clinical trials, sotalol was registered first in Europe but its sales were dwarfed by propranolol. In later years, probing clinical research established a significant...