Inhibitor development

Collie, M. J. (ed.). Corrosion Inhibitors Developments Since 1980, Chemical Technology Review No 23, Noyes Data Corporation, New Jersey (1983)... 

MMP inhibitor development constitutes an important branch of research in both academic and industrial settings and advances our knowledge on the structure-function relationship of these enzymes. Targeting... 

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

The third NS3/4A inhibitor developed was SCH 503034 (boceprevir). This inhibitor also uses the keto-amide strategy to form a covalent bond with Serl39, and in this case representing a P1-P3 mimetic, although the P3 capping group occupies S4 (Venkatraman et al. 2006). An initial phase 1 dosing smdy showed potency in humans which was enhanced with coadministration of interferon-a (Sarrazin et al. 2007). 

In the following sections, an overview of some of the key developments in the discovery of potent influenza vims sialidase inhibitors is provided. In the first instance, the discovery of the influenza vims sialidase inhibitors that have become the current first-hne-of-defence anti-influenza dmgs will be described, followed by a description of some of the other important sialidase inhibitor developments to date. 

The development of sialidase-based inhibitors as anti-influenza drugs has provided a first line-of-defence to safeguard humanity against a potential pandemic and most importantly to buy time for vaccine and further anti-influenza drug development. Most exciting is that new opportunities exist for next generation sialidase inhibitor development. 

Kelly WK, Marks PA (2005) Drug insight histone deacetylase inhibitors - development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2 150-157... 

The standard model for the preclinical development of anti-osteoporosis therapies is the ovariectomized (OVX) rat. However, Cat K inhibitors developed specifically against the human enzyme are generally significantly less potent ( 2-orders of magnitude) against the rat and mouse enzymes than against human Cat K [9]. This loss of potency towards the rodent enzymes, which is consistent with their low sequence homology, therefore restricts the use of... 

Tabata S, et al. Anti-tumor mechanisms of 3 -ethynyluridine and 3 -eth5mylcytidine as RNA synthesis inhibitors development and characterization of 3 -etyh5niyluri-dine-resistant cells. Cancer Lett 1997 116 225. 

Jones P, Steinkuhler C. (2008) From natural products to small molecule ketone histone deacetylase inhibitors Development of new class specific agents. Curr Pharm Des 14 545-561. 

Fig. 11. These two HDAC inhibitors developed by Jones and coworkers with apicidin structure as the inspiration.

Tenidap (Figure 8.26) is a dual cyclooxygenase (COX) and 5-lipoxygenase (5-LPO) inhibitor developed as an anti-inflammatory agent. Severe abnormalities in hepatic function were reported in Japanese clinical trials [28]. Although the thiophene is not directly implicated in these findings, the ready activation of this system to potential reactive metabolites may be suggestive of the involvement of this function. 

Goedert M, Cohen P. GSK3 inhibitors development and therapeutic potential. Nat Rev Drug Discov 2004 3 479-87. 

Figure 9.11 Selective tubulin and histone deacetyiase inhibitors developed by Schreiber.

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

With the recognition in the late 1960s that there are two forms of MAO (Section 1.1.1), potential therapeutic implications related to isozyme selectivity needed to be considered in MAO inhibitor development. (The early literature also reveals some lack of distinction between copper-containing and flavin-containing MAOs.) An important case in point involves the clinical side effects associated with the cheese effect (Section 1.2.1) that made clear that there would be important clinical advantages to having available isozyme-selective inhibitors [115]. Follow-up studies with the well-known cyclopropylamine inhibitor trans-2-phenylcyclopropylamine (8a) demonstrated that this clinically useful compound is an irreversible inhibitor of MAO, but that it had no selectivity toward either MAO A or B [116]. 

Venlafaxine is one of the first selective serotonin and norepinephrine reuptake inhibitors developed for the treatment of depression. It was originally released in the United States in 1994. 

A similar strategy has been used to optimize a number of peptide-based compounds with therapeutic potential, including tachykinins, enkephalins, and protease inhibitors. HIV protease is essential for producing mature, infectious virus, and two protease molecules are carried in each mature virion (Figure 4.7). With inhibitors developed specifically for HIV protease, but not human protease, one hopes to halt virus replication. Peptides with HIV protease inhibitor activity have been further refined by means of computer- and structure-based design strategies, leading to the development of new molecular entities that are stable to proteases and compact so that they can be administered orally (Table 4.6). Some protease inhibitors (e.g., ritonavir and... 

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