Pyridine isosteres

Pirbuterol is the pyridine isostere of albuterol. It has pharmacokinetics similar to albuterol but is half as potent at the p2-receptor. Pirbuterol is only available as an inhaler, whereas albuterol comes in tablet, syrup, solution, and aerosol formulations. Adverse effects of pirbuterol are nervousness, tremor, and headache, which is less than the profile for albuterol, which adds nausea, vomiting, dizziness, hypertension, insomnia, tachycardia, and palpitations. 

Erlenmeyer and Schmid (459), in the course of a fundamental comparison between pyridine and its isosteric thiazole structures, prepared the... 

Thiazoles are less electron-rich isosteres of pyridines and therefore it was speculated that compounds with such substitution may have improved metabolic stability [30]. The modeling of A-82200 in which the N-terminal pyridinyl group was substituted by a 4-thiazolyl moiety indicated that the 5-membered ring binds in the S3 subsite and can be further derivatized at the 2 position by an isopropyl group. The isopropyl functionality makes van der Waals contacts with Val82 and fills the hydrophobic part of the S3 subsite in nearly optimal fashion. 

Benzene (33) is isosteric with pyridine (34) and thiophene (35) because the -CH=CH- group is isosteric with -N= and -S- atoms. Although these substances are structurally different, some of their chemical properties are nonetheless similar. All of them are aromatic, all are liquid, and all are about equal in molecular size and volume. In fact, both 33 and 35 boil at about 81 °C. 

Monocyclic l,2-dihydro-l,2-azaborines (3) easily form polymers with the exception of the 2-phenyl derivative (109 R = Ph), probably because of interaction between the two rings. In contrast, the alkyl substituted monocyclic system (155) is stable towards polymerization although it is easily oxidized by air and hydrolyzed by water. This stability order between (3) and (155) was predicted by semi-empirical methods. However, the ring system (7), isosteric with pyridine, seems to be the most stable of the monocyclic systems. Some of its alkyl derivatives remain unchanged after 50 h in concentrated sulfuric acid at 80 °C. After reflux in 1M sodium hydroxide almost all of the compound was recovered. 

Deuteration in deuteriosulfuric acid of some derivatives of thieno fused diazaborines was studied by NMR spectroscopy. It was found that the pyridinic nitrogen was protonated and that deuteration occurred in the thiophene ring of the protonated molecule. In conformity with the above-mentioned electrophilic substitutions, the thiophenic /3-positions were more reactive than the a-positions. Isosteric thienopyridines showed similar reactivity and it was thus concluded that the systems were related (77JHC893). 

In a series of substituted 2-arylpyrrolidines in which the substituted aryl group is a bio-isosteric replacement for the pyridine ring of nicotine, it was found that the isoxazole derivative (69) is a potent cholinergic channel activator (116). 

Synthesis of the Thiono Isostere of Imazethapyr. The thiono isostere of imazethapyr was prepared in the same fashion from 5-ethyl-pyridine-2,3-dicarboxylic anhydride 13. The resulting mixture of regioisomers 14 and 15 was treated with aqueous sodium hydroxide to afford acid 16 after acidification and fractional crystallization. 

Gezginci MH, Martin AR, and Franzblau SG. Antimycobacterial Activity of Substituted Isosteres of Pyridine- and Pyrazinecarboxylic Acids. J Med Chew 2001 44 1560-1563. 

HIF-la prolyl hydroxylase (EGLN-1) The X-ray analysis of EGLN-1 in complex with an isoquinoline derivative inspired the design of a series of pyridine carboxyamide derivatives which could then be further improved by replacing the flexible carboxyamide substituent with a constrained isostere, pyrazole carboxylic acid. 139 ... 

Morales and KooP " have used a set of non-polar isosteres of natural DNA bases to probe the interactions at the active site of a number of different polymerases by replacing the deoxynucleoside analogues of difluorotoluene (F) for thymidine and 4-methylbenzimidazole (Z) or 9-methyl-l-if-imidazo[4,5-fe] pyridine (Q) (129) for adenosine. Their findings showed that each polymerase, Klenow (exo ) fragment, Taq, T7 and HIV-RT, were all able to efficiently generate the non-natural base-pairs A-F, F-A, F-Z and Z-F. Calf thymus DNA... 

Oxazolidines 30 and oxazinanes 31, depending upon the nature of their C-2 substituents, could react with 1,3-dicarbonyl systems which have considerable enolic tautomer components in 1 2 or 1 1 stoichiometry in a manner analogous to their reactions with enamines to form oxygen isosteres of pyridine derivatives (96T14273). 

These reactions are very interesting from the point of view of synthesis of novel heterocyclic compounds. Analogs are not found in the isosteric car-benes, however. 2-Diazomethylpyridine N-oxides (330) give rise to 2-acyl-pyridines (332) by photolysis or thermolysis.373,374 In view of the surprisingly facile formation of cyclobuta[de]naphthalene from 1-naphthylcarbene (see Eq. 69) the intermediate 10 jr-electron pyridooxazete 331 does not seem unreasonable (Eq. 94). Other pathways are possible too, however.273... 

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