Urea isosteres

To further explore the role of the furan motif on chemokine receptor binding, functional activity as well as oral exposure in rats, Yu et al. found that the furyl series, and in particular 4-halo analogs, possessed superior in vitro and in vivo properties compared to a broad panel of other heterocyclic ring systems [115]. Interestingly, the SAR obtained in these studies illustrated once more the tolerant nature of CXCR2 versus the more sensitive CXCRl vhth respect to structural but also electronic factors. 

25 afforded nice binding affinities I]-CXCL8 CXCR2 Ki 14 nM, CXCRl Ki 91 nM) but also functional activity comparable to 23 [117]. 

---

Recent reports have emerged of several TRPV1 antagonists possessing a biaryl amide (14-16), urea (17), or urea isostere (18-20) scaffolds. Bicyclic derivatives 14-16 block capsaicin- or pH-stimulated calcium influx in FLIPR-based assays... 

Other interesting hybrids between hydroxyethylene and hydroxyethylamine dipeptide isosteres have been reported. Getman et al (1993) developed a series of hydroxyethylureas that potently inhibited HIV-1 protease. The concept of these urea isosteres, first introduced as renin inhibitors, may be envisioned as a modification of the hydroxyethylene isostere (e.g., compound 22), in which the PV chiral a-car-bon is replaced with a trigonal nitrogen. One example of this class of inhibitors, SC-52151 (26) (Table III), inhibited HIV-1 protease with an IC50 value of 6 nMand blocked the cytopathic effect of HIV-1 in cell cul-... 

QSAR 50 was reported [14] for a series of compoimds containing R-hydroxyethyl urea isostere (42) studied by Getman et al. [162]. Replacement of the PI chiral or-carbon center of the hydroxyethylene isostere with trigonal nitrogen gives a urea isostere (Fig. 11b) [158]. 

Fig. 12 Schematic representation of binding of a hydroxyethyl urea isostere with hydrophobic regions of HIV protease (Reprinted with permission from [162]. Copyright 1993 American Chemical Society)...

It will be noted that Na is isosteric with the tetradeprotonated urea molecule, (H2N)2C=-0, and is also isoelectronic and isostructural with and N03. An X-ray analy-... 

Replacement of the carbamate group with isosteric functionalities such as an IV-methyl carbamate, urea, or amide group clearly confirmed the favorable qualities of the carbamate group [57], While the introduction of a urea group, as in case of iV-9-(tert-butylcarbamoyl)-9-desoxy-9-aminoquinine selector, instead of carbamate functionality turned out to be virtually equivalent in terms of enantiorecognition capabilities [57,58], the enantiomer separation potential was severely lost on iV-methylation of the carbamate group, like in 0-9-(N-me hy -N-tert-butylcarbamoyl)quinine [32,58], or its replacement by an amide, such as in case of Af-9-(pivaloyl)-9-desoxy-9-aminoquinine selector [57,58], For example, enantioselectivities dropped for DNB-alanine from 8.1 for the carbamate-type CSP, over 6.6 for thein-ea-type CSP, to 1.7 for the amide-type CSP, and 1.3 for the A -methyl... 

Recently, Kelly and Kim have compared the relative binding affinities of urea and bisurea 33 and 34 with carboxylate and its isosteres. They find that both hosts preferentially associate with functionalities according to the following ranking ArOPO - > ArPO - > ArCOj > ArP(OH)02 > Ar0P(0H)02 > ArSOj > ArSOj 5-lactone > ArNOj. 

The objective of this study is to evaluate which features of activated carbon surfaces are important for adsorption of acetaldehyde. The evaluation is based on the values of isosteric heats of adsorption, which reflect the strength of molecule interactions with the sorbent surface. After oxidation and urea modification the changes in surface chemistry and porous structure occurred. Those changes are expected to affect the dispersive and specific interactions of acetaldehyde with the activated carbon surfaces. 

Workers at DuPont used a pharmacophore model and database search to develop the first type III mimetic inhibitor of HIV protease, DuP450 (87)(Fig. 15.38). This evolved from a 3D pharnacophorethat retained two key interactions replacement of the flap-bound water and a hydroxyl transition-state isostere (155). Molecular modeling led to a cyclohexanone as a better spacer between these groups, and finally the seven-membered cyclic urea (87) was created (Fig. 15.38). The development of these inhibitors illustrates the importance of conformational analysis in the design of constrained analogs. 

It will be noted that N a " is isosteric with the tetradeprotonated urea molecule, (H2N)2C= O, and is also isoelectronic and isostructural with CO3 and N03 . An X-ray analysis of the red single crystals shows that N(central)-N is long (149 pm) and that N(central)-Nt is short (123 pm). Linbranched N-catenation is observed in 2-tetrazcncs such as (Mc3Si)2N-N N-N(SiMe3)2 (mp 46°) and its derivatives, e.g. 

Carbamic acid, 0=C(0H)NH2, can be regarded as derived from carbonic acid by substitution of —NH2 for —OH. This is only one example of the existence of compounds that are related in this way —NH2 and —OH are isoelectronic and virtually isosteric and frequently give rise to isostructural compounds. If the second OH in carbonic acid is replaced by NH2, we have urea. Carbamic acid is not known in the free state, but many salts are known, all of which, however, are unstable to water, because of hydrolysis h2ncoi +h2o -> NHi +CO -... 

Inosine monophosphate dehydrogenase (IMPDH) is an enzyme in the de novo synthetic pathway of guanosine nucleotides. Pitts et al. have identified several series of novel triazine inhibitors of the enzyme IMPDH II. These compounds demonstrate that the urea or diamide isosteres can be replaced effectively by heterocycles <2002BML2137>. 

Sulfamic acid, NH2SO3H, is an ammonoaquosulfuric acid in which one of the hydroxyl groups of sulfuric acid has been replaced by the isosteric amido group. It is prepared commercially by the interaction of fuming sulfuric acid and urea. This method is not readily adaptable to laboratory preparation on a small scale. Consequently, the sulfur dioxide-hydroxylamine reaction is recom-mended.H Sulfamic acid may also be obtained by the action of sulfur dioxide upon certain compounds which yield hydroxylamine such as acetoxime. The recommended procedures are modifications of older processes and involve the use of sulfur dioxide under pressure upon aqueous solutions of hydroxylammonium salts and compounds yielding hydroxylamine. 

All the US-FDA approved Pis except Tipranavir (7) are substrate-based peptidic inhibitors. These inhibitors were designed using the "transition state peptidomimetic principle, which means that in the inhibitors the hydrolyzable peptide linkage is replaced by a non-hydrolyzable transition-state isostere (Fig. 11a) [158]. A munber of such isosteres were studied including statin, norstatin, hydroxyethylene, reduced amide, hydroxyethylamine, hydroxyethyl urea, monoalcohol, diol and aminodiols (Fig. 11b) [158]. Various classes of inhibitors containing dihydroxyethylene transition state isosteres were extensively developed. As an alternative to the peptide-based approach penicillin-derived C2 symmetric compounds were also pursued. 

ILIAD ate linear sequences built up from five units, taken from the components listed in Figure 26. The id that a-hydrocarbon-can-mimic-anything is evident in this design as well, although we incorporate sulfide and disulfide because of their unique bond angles and dihedral angles. The "trimethylenemethane" unit is included as an isostere for urea and carbamate units, and the "cyclopentadienyl" moiety is an isostere for five-membeied ring aromatic heterocycles. 

---