Reminiscences of the development of cimetidine

Duncan, W. A. M.; Parsons, M. E.

doi:10.1016/0016-5085(80)90880-x

Cited by 24 publications

(4 citation statements)

References 4 publications

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“…Only little differences in the potency between the derivatives were seen, depending on the ring size and the character of the condensed ring (Table 2). The phenylthiophene (31) and the 3-methylthiophene derivative (32) as well as the 2,3-dihydrobenzo[b] [1,4]dioxin containing compound (33) were of comparable potency. Only a little decrease of the potency was observed in the case of an extension or reduction of the attached saturated ring (34,35).…”

Section: Resultsmentioning

confidence: 99%

“…In this manuscript we describe further development of QC inhibitors by means of a structure-based approach utilizing a homology model of the enzyme. Furthermore, new active compound classes could be identified by the bioisosteric replacement of the unfavorable thiourea moiety. − The efficacy of the compounds regarding their ability to suppress pGlu formation at the N-terminus of the Aβ-peptide was shown in a cell-based model.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, new active compound classes could be identified by the bioisosteric replacement of the unfavorable thiourea moiety. [27][28][29][30][31] The efficacy of the compounds regarding their ability to suppress pGlu formation at the N-terminus of the Aβ-peptide was shown in a cell-based model. *To whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors for Human Glutaminyl Cyclase by Structure Based Design and Bioisosteric Replacement

Buchholz¹,

Hamann²,

Aust³

et al. 2009

J. Med. Chem.

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The inhibition of human glutaminyl cyclase (hQC) has come into focus as a new potential approach for the treatment of Alzheimer's disease. The hallmark of this principle is the prevention of the formation of Abeta(3,11(pE)-40,42), as these Abeta-species were shown to be of elevated neurotoxicity and likely to act as a seeding core leading to an accelerated formation of Abeta-oligomers and fibrils. Starting from 1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thiourea, bioisosteric replacements led to the development of new classes of inhibitors. The optimization of the metal-binding group was achieved by homology modeling and afforded a first insight into the probable binding mode of the inhibitors in the hQC active site. The efficacy assessment of the hQC inhibitors was performed in cell culture, directly monitoring the inhibition of Abeta(3,11(pE)-40,42) formation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitors for Human Glutaminyl Cyclase by Structure Based Design and Bioisosteric Replacement

Buchholz¹,

Hamann²,

Aust³

et al. 2009

J. Med. Chem.

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“…They hypothesized that the best assays and disease models identified good drugs, which succeeded in clinical trials, entered widespread clinical use, became generic, raised the commercial barriers to new R&D, and so rendered the best models industrially redundant. Think, for example, of models of stomach acid secretion 21,22 and the safe and effective H2 receptor antagonists and proton pump inhibitors that they identified. Poor assays and models, on the other hand, failed to identify enough good drugs so, ironically, remained in widespread use, sometimes for decades.…”

Section: [H1] Importance Of Decision Tool Validitymentioning

confidence: 99%

Predictive validity in drug discovery: what it is, why it matters and how to improve it

Scannell

Bosley²,

Hickman³

et al. 2022

Nat Rev Drug Discov

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Successful drug discovery is like finding oases of safety and efficacy in chemical and biological deserts. Screens in disease models, and other decision tools used in drug research and development (R&D), point towards oases when they score therapeutic candidates in a way that correlates with clinical utility in humans. Otherwise, they probably lead in the wrong direction. This line of thought can be quantified by using decision theory, in which 'predictive validity' is the correlation coefficient between the output of a decision tool and clinical utility across therapeutic candidates. Analyses based on this approach reveal that the detectability of good candidates is extremely sensitive to predictive validity, because the deserts are big and oases small. Both history and decision theory suggest that predictive validity is under-managed in drug R&D, not least because it is so hard to measure before projects succeed or fail later in the process. This article explains the influence of predictive validity on R&D productivity and discusses methods to evaluate and improve it, with the aim of supporting the application of more effective decision tools and catalysing investment in their creation.

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Inhibitors of Gastric Acid Secretion

Roberts¹,

McDonald²

2003

Burger's Medicinal Chemistry and Drug Discovery

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The discovery of potent and selective inhibitors of gastric acid secretion now negates the need for surgical intervention in the treatment of many hypersecretory disorders. The side effects associated with cholinergic antagonists has led to their being superseded by the use of selective histamine H 2 ‐receptor antagonists (cimetidine, ranitidine, famotidine) and the more potent irreversible proton‐pump inhibitors (omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole). Current therapeutic regimes for the treatment of ulcer disease recommend concurrent proton‐pump administration while eradicating Helicobacter pylori , a bacterial infection that is strongly associated with ulcer formation. Because achlorhydria increases the likelihood of gastrointestinal infection, current research within this area is now targeting the design of reversible proton‐pump inhibitors and CCK 2 /gastrin‐receptor antagonists. These newer therapeutic approaches, however, are unlikely to produce the rapid and potent inhibition of acid secretion realized by the irreverisble PPIs, which in addition have few side effects and a proven track record of success. Key drug developments in the treatment of acid hypersecretion, from the anticholinergic agents to the highly potent and effective proton‐pump inhibitors currently in use, are covered in this chapter.

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Reminiscences of the development of cimetidine

Cited by 24 publications

References 4 publications

Inhibitors for Human Glutaminyl Cyclase by Structure Based Design and Bioisosteric Replacement

Inhibitors for Human Glutaminyl Cyclase by Structure Based Design and Bioisosteric Replacement

Predictive validity in drug discovery: what it is, why it matters and how to improve it

Inhibitors of Gastric Acid Secretion

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