Imidazopyridines, structure

Similarity to the benzimidazole synthesis led sometimes to an erroneous assignment of an imidazopyridine structure to acyl derivatives of o-DAPs. Thus, Garmaise and Komlossy (64JOC3403) indicated that Takahashi and Yajima (46JPJ31) believed the products they had prepared by acylation of 2,3-DAP with aromatic acid anhydrydes really had the IP structure. Moreover, it was revealed that the reaction between u-DAP and anthranilic add afforded merely a salt of these compounds. 

The narrow therapeutic range of digitalis related cardiotonic agents has resulted in an extensive effort to identify compounds in other structural classes which will improve cardiac function. The discovery of the heterocyclic cardiotonic drug, amrinone, led to research on other heterocyclic compounds for that indication. The imidazopyridine, isomazole (57), is representa-... 

It was known that the K+ -competitive imidazopyridine compound, SCH28080, inhibits acid secretion. Then, many reversible inhibitors were developed. These contain protonatable nitrogens but have a variety of core structures such as imidazopyiidines, piperidinopyr-idines, substituted 4-phenylaminoquinolines, pyrrolo [3,2-c]quinolines, guanidinothiazoles, and 2,4-diamino-pyrimidine derivatives. Several reversible inhibitors have been in clinical trials. 

Fig. 3.10 Recognition of the DNA minor groove with benzimidazole derivatives, (a) Structure of the dimeric core for Py-benzimi-dazole (Bi), Py-hydroxybenzimidazole (Hz) and Py-imidazopyridine (Ip) (left) in comparison with the five-membered ring system (right). H-bonding surfaces along the recogni-...

The term benzodiazepine refers to a specific chemical structure. Numerous benzodiazepine-receptor ligands exist which have different structures. These include the jS-carbolines (e.g. methyl-6,7-dimethoxy-4-ethyl-jS-carboline 3-carboxylate DMCM), triazolopyridazines (e.g. CL 218872), imidazopyridines (e.g. zolpidem), and pyrazolo-quinolinones (e.g. CGS 8216). In experimental animals these compounds produce... 

Figure 19.6 The chemical structure of the imidazopyridine and benzodiazepine (BZi) receptor ligand, zolpidem, and the cyclopyrrolone, zopiclone...

Potent IRAK-4 inhibitors have been reported by several groups including some structurally related benzimidazoles (e.g., 34-36) as well as alternative fused heterocycles such as the imidazopyridine (37) and imidazopyridazine (38) [102-107]. Such compounds are... 

Zolpidem (an imidazopyridine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, possess agonist activity at the benzodiazepine receptor (p. 226). 

The search for viable partial agonists or subtype selective ligands has led to the development of a variety of compounds representing diverse structural types including imidazoquinoxalines, benzodiazepines, imidazopyridines and -carbolines. In an effort to identify replacement candidates for the partial agonist pandiplon U 78875 206 [289], which was removed from clinical trials due to... 

Zolpidem is an imidazopyridine, with a chemical structure of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo [ 1,2-alpha] -pyridine-3-acetamine hemitartrate (Salva and Costa, 1995). This nonbenzodiazepine sedative hypnotic was first released in Europe, and then introduced in the United States in 1993 (Hobbs et ah, 1996). Zolpidem has a strong sedative effect that seems to preclude its use as an anxiolytic. It has only weak anticonvulsant effects (Salva and Costa, 1995 Hobbs et ah, 1996). 

That the benzodiazepine structure was a prerequisite for the characteristic tranquilizer profile and specific binding at the benzodiazepine receptor was a long-held belief. This has now been shown not to be the case by the discovery of a range of different compounds that bind to the benzodiazepine receptor [Figure 29-2). These include the 3-carbolines (e.g., abecarnil), the triazolo-pyridazines [e.g., GL 218,872), the imidazopyridines (e.g., zolpidem), the cyclopyrrol ones [e.g., suriclone), and the pyrazoloquinolines. 

As reported in <1996GHEC-II(7)283>, no specific study on the mass spectra of these classes of compounds has been reported, although this analytical method has only been used as a tool for structure elucidation or reference without critical analysis. Some examples are reported in <1996GHEC-II(7)283>. Further information on the MS of heterocycles can be found in <2001MI1>. The mass spectral data for imidazopyridines, pyrazolo[3,4- ]pyridines, oxazolo-pyridines, ioxazolopyridines, isothiazolopyridines, 377-1,2-dithiolo[3,4- ]pyridines, and l,3-dithiolo[4,5- ]pyridines were reported in <1996GHEG-II(7)283>, but there have been no further reports in this area. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

Zolpidem (an imidazopyridine), zale-plone (a pyrazolopyrimidine) and zopi-clone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, can bind to the benzodiazepine site on the GABAa receptor (p. 222). However, their effects do not appear to be identical to those of benzodiazepines. Thus, compared with benzodiazepines, zolpidem exerts a weaker effect on sleep phases, supposedly carries a lower risk of dependence, and appears to have less anxiolytic activity. Heterogeneity of GABAa receptors may explain these differences in activity. GABAa receptors consist of five subunits that exist in several subtypes. 

Zolpidem is an imidazopyridine in structure and has a fast onset (30-60 min) and short duration of action. Patients over 80 years have slower clearance of this drug. 

A number of compounds that have. structural characteristics broadly related to the benzodiazepines, including neuro-active flavanoids, imidazopyridines. and pyrazolopyriniid-iiKs. can act as positive mc ulators at the benzodiazepine recognition site on one or more of the GABAa receptor mbtypes. Compounds may produce all the characteristic actions of benzodiazepines or be selective, as are. for example, anxiolytic flavanoids or the. sedative-hypnotics zolpidem and zalephun. 

In terms of structure, compounds which bind to the BZD site are generally flat, and contain a two or three-ring heterocyclic nucleus at their core. They include the BZDs mentioned previously, /I-carbolines (e.g. abecarnil, 12), imidazopyridines (e.g. alpidem, 13), pyrazoloquinolines (e.g. CGS 8216, 14), and imidazoquinoxalines (e.g. panadiplon, 15). New series of compounds with BZD site affinity are regularly reported in the medicinal chemistry literature [38-41] with similar overall structural elements. There are... 

Omeprazole, lansoprazole, and related analogues (Table 37.11), produce inhibition of stimulated gastric acid secretion irrespective of the receptor stimulation process. Nearly al the compounds are close structural relatives, being weakly basic 2-pyridylmethylsulfinylbenzimidazoles. An analogue, tenatoprazole, which is an imidazopyridine isostere, is currently in clinical trials. 

Molecules of imidazopyridines 1 and 2 (IP) are built from imidazole and pyridine nuclei that have no common nitrogen atom. This distinguishes imidazopyridines 1 and 2 from imidazo[l,2-a]pyridine 2 and imidazo[l,5-a]pyridine 6. The latter two have little in common with purine in terms of molecular structure and chemical properties (66JOC1295, 67JOC2430). Consequently, imidazopyridines 5 and 6 are not analogues of purine and are not considered here. 

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