Pyridine inhibitor

Among the few reported inhibitors, the optimized HTS lead phe-nylimidazole 39 is an interesting candidate against S. pneumoniae with nanomolar FabK inhibition and an MIC90 of 4 pg/mL [59]. The same team hybridized 29, a FabI pyridine inhibitor with 39 to provide 40, in an attempt to realize a compound with a dual mode of action. Although inhibition of both enzymes as well as sub-pg/ mL MIC against S. pneumoniae is retained, the Fabl-related antibacterial activity against S. aureus is lost [60]. 

Other applications of zirconium tetrafluoride are in molten salt reactor experiments as a catalyst for the fluorination of chloroacetone to chlorofluoroacetone (17,18) as a catalyst for olefin polymerization (19) as a catalyst for the conversion of a mixture of formaldehyde, acetaldehyde, and ammonia (in the ratio of 1 1 3 3) to pyridine (20) as an inhibitor for the combustion of NH CIO (21) in rechargeable electrochemical cells (22) and in dental applications (23) (see Dentalmaterials). 

Metal Cleaning. About 204 thousand metric tons of HCl (100% basis) was consumed in 1993 for steel pickling, wherein the hydrochloric acid readily dissolves all of the various oxides present in the scale formed during the hot rolling process. Using suitable inhibitors such as alkyl pyridines, HCl reacts very slowly with the base metal rendering the surface so clean that it must be passivated with a mild alkaline rinse. 

This technique can be applied to prepare DL-a-fluoromethylputrescme (5-fluoropentane 1,4-diamine), a potent irreversible inhibitor of E colt ornithine decarboxylase, from 4-phthalimido-l -butyryl chloride, diazomethane, and hydro gen fluonde-pyridine [94 95]... 

The dinitro derivative of compound 2 reacts with anhydro bases of pyridine and quinoline to give zwitterions such as 215 (99RCB1391). Compound 216 has been made from the 3-bromo derivative of compound 3 by reaction with an amine, as an intermediate in the production of stomach secretion inhibitors (80EUP48555),... 

N— compounds used as acid inhibitors include heterocyclic bases, such as pyridine, quinoline and various amines. Carassiti describes the inhibitive action of decylamine and quinoline, as well as phenylthiourea and dibenzyl-sulphoxides for the protection of stainless steels in hydrochloric acid pickling. Hudson e/a/. refer to coal tar base fractions for inhibition in sulphuric and hydrochloric acid solutions. Good results are reported with 0-25 vol. Vo of distilled quinoline bases with addition of 0 05m sodium chloride in 4n sulphuric acid at 93°C. The sodium chloride is acting synergistically, e.g. 0-05m NaCl raises the percentage inhibition given by 0-1% quinoline in 2n H2SO4 from 43 to 79%. Similarly, potassium iodide improves the action of phenylthiourea . 

In the former Soviet Union much use is made of industrial by-products to prepare acid inhibitors. The PB class is obtained by treating technical butyraldehyde with ammonia and polymerising the resulting aldehyde-ammonia. PB-5, for example, with O-Ol-O-15% of an arsenic salt is used in 20-25% HCl. A mixture of urotropine (hexamethyleneimine, hexamine) with potassium iodide, a regulator and a foaming agent is the ChM inhibitor. BA-6 is prepared from the condensation product of hexamine with aniline. A more recent development is the Katapin series which consists of /7-alkyl benzyl pyridine chlorides Katapin A, for example, is the /7-dodecyl compound. 

Direct measurements on metals such as iron, nickel and stainless steel have shown that adsorption occurs from acid solutions of inhibitors such as iodide ions, carbon monoxide and organic compounds such as amines , thioureas , sulphoxides , sulphidesand mer-captans. These studies have shown that the efficiency of inhibition (expressed as the relative reduction in corrosion rate) can be qualitatively related to the amount of adsorbed inhibitor on the metal surface. However, no detailed quantitative correlation has yet been achieved between these parameters. There is some evidence that adsorption of inhibitor species at low surface coverage d (for complete surface coverage 0=1) may be more effective in producing inhibition than adsorption at high surface coverage. In particular, the adsorption of polyvinyl pyridine on iron in hydrochloric acid at 0 < 0 -1 monolayer has been found to produce an 80% reduction in corrosion rate . 

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

Anodic inhibitors limit the oxidation of iron by sharing the lone pair electrons on the nitrogen with a metal ion or atom and supressing the anodic reaction. Examples are benzotriazole (at high concentrations), pyridines, thiols, and quinolines. 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

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). 

High density brine completion fluids also often require the use of corrosion inhibitors (8,9). Blends of thioglycolates and thiourea alkyl, alkenyl, or alkynyl phosphonium salts thiocyanate salts mercaptoacetic acid and its salts and the reaction products of pyridine or pyrazine derivatives with dicarboxylic acid monoanhydrides have been used as high density brine corrosion inhibitors. 

The incorporation of an ionizable center, such as an amine or similar function, into a template can bring a number of benefits, including water solubility. A key step in the discovery of the protease inhibitor, indinavir was the incorporation of a basic amine (and a pyridine) into the backbone of hydroxyethylene transition state mimic compounds L-685,434 to enhance solubility (and potency) (Fig. 1.2) [17]. 

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]. 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3-dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloro-iV,jV-dimethyl-armnotrimethinium hexafluorophosphate afforded 8 in 97% yield . Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. 

---