Other chemotypes

One promising approach to identify novel CFTR corrector structural classes is to screen compounds, already developed for other indications, for their ability to correct the trafficking defect of mutant CFTR. Following this approach, glafenine hydrochloride (17), miglustat (18), and SAHA (19) were recently described as promising CFTR corrector leads. 

Ester 17, which is nonsteroidal and anti-inflammatory, partially corrected the defective processing of F508del-CFTR in vitro in multiple cell lines (BHK, HEK-293, and CFBE41o- human airway epithelial cells) 

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Mankind evolved and came to use all possible chemical combinations of elements, energy sources, and communication means to make every type of device in external space and to control all life forms consistent with mankind s desires and advancement. In effect one species became a new chemotype. In principle mankind is the final chemotype but it is the most dependent of all on basic chemicals of all other chemotypes. 

JMJD2 demethylases are inhibited by analogues of the cofactor 2-OG that include N-oxalylamino acids, pyridine dicarboxylates, and related bipyridyl derivatives. Other chemotypes that are also presumed to bind to the active-site Fe(II) include catechols, hydroxamic acids (including the clinically used HD AC inhibitor SAHA/Vorinostat), and tricarboxylic acid cycle intermediates, such as succinate and fumarate [59,62]. 

Other Chemotypes. Several other 5-HT, antagonists have demonstrated cognition-enhancing effects in animal models. However, data from human studies have yet to be reported. (i2)-Zacopride (170 in Fig. 14.18 Synthelabo) is undergoing clinical development as a potential treatment for cancer chemotherapy-induced emesis. In atropine-treated rats, (jR)-zacopride significantly attenuated memory impairments in a spatial navi-... 

At least two other chemotypes, tetrahydroquinolines (Fig. 25.1.5, 25 [87-88]) and amidoketones (Fig. 25.1.5, 26 [89, 90] also reviewed in Ref. [6]) have been shown to directly (ligand binding assays) or indirectly (cell based reporter gene transactivation assays) interact with the ecdysone receptor. These new ecdysone receptor binding chemistries could lead to new products for control of insect pests not controlled by current BAH insecticides. 

Many of the early QSAR-driven methods made assumptions about the behavior of the datasets to be studied and/or generated. A significant assumption is one of additivity—the effect of a substituent is constant when combined with all other types of substituent or when added to all other chemotypes. This was quickly found to be untrue in many cases. An example is two series of H2-antagonists, which both gave rise to marketed drugs (ranitidine and cimetidine) [16], shown in Figure 8.5. 

Douglas, M, H, J, W, van Klink, B. M. Small eld, N, B. Perry, R. E. Anderson, P. johnstone, and R, T, Weavers, 2004, Essential oils from New Zealand manuka Triketone and other chemotypes of Leptospermum scoparium. 1255-1264,... 

Douglas, M.H. et al. (2004) Essential oils from New Zealand manuka triketone and other chemotypes of Leptospermum scoparium. Phytochemistry 65, 1255-1264... 

Rosemary oil is obtained from flowering tops and leaves of Rosmarinus officinalis L. (evergreen shrub, Lamiaceae) with the yield of 0.5-2.5%. It is clear, mobile, colorless to pale yellow liquid with a characteristic odor. The main use of the oil is in seasoning blends. Two types of rosemary oil are available on the market, that differ mainly in percentages of main constituents, although several other chemotypes are known. 

Myrtaceae), known locally as kanuka. Fifty-one specimens from New Zealand along with six from Australia (and other species of Kunzea) were included in the study. Oils from Australian and New Zealand specimens were quite similar with a-pinene as the most prominent component in both, along with lower but similar levels of p-cymene and 1,8-cineole. Although two chemotypes can be defined within this taxon, they occur within populations and do not show the geographic patterning seen in manuka. 

An interesting dispersal scenario was described by the authors on the basis of the similarity of southern Finnish chemotypes to chemotypes found in the Netherlands, and other parts of Northern Europe. They suggest that tansy seeds, known to be common components of shipping ballast (Jutila, 1996), may have been transported to... 

Kirch et al. (1995) examined individual plants collected in Corsica, Elba, Sardinia, Liguria, and Provence for alkaloids and observed four groups, one characterized by sparteine [119] (see Fig. 2.34 for structures 119-124), one characterized by lupanine-based alkaloids [120 and 121], one that had a very low level of alkaloid production, and one that lacked sparteine and lupanine-based compounds, but did accumulate other alkaloids such as anagyrine [122], ammodendrine [123], and compounds based on cytisine [124], their outlier group. The distribution of these four chemotypes is presented in Table 2.10. 

The second chemotype (their Type 1) had, in addition to the Type 0 array, substantial amounts of a-longipinene [297] and an unidentified sesquiterpene alcohol. The third chemotype (their Type 2) was distinguished by the presence of, among other compounds, cedrene isomers, [a-cedrene is shown as 298], and large amounts of the isomeric sesquiterpene alcohols a-acorenol [294] and its P-isomer [295]. The acora-diene isomers [295 and 296] were also identified. Some geographic patterning was observed in the Type 0 chemotype when the data were subjected to numerical analysis a trend in the reduction of caryophyllene content was revealed in a west to east direction. The data sets for Types 1 and 2 were too small to allow for similar analysis. 

Recent work identifying Plagiochila retrorsa Gottsche from collections made in the Azores and Madeira establishes a significant range extension for a taxon, known under several other names, which occurs in the southern Appalachian Mountains and in Costa Rica. Rycroft et al. (2001) described morphological and phytochemical characteristics of representative specimens of this liverwort. Phytochemically, P. retrorsa belongs to the 9,10-dihydrophenanthrene chemotype species (major stmctural type is that of compounds 449 and 450). 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

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