Hydrogen bonding bioisosteric replacement

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

Numerous results have demonstrated that the free 2 -OH is crucial to the activity. Its replacement with other bioisosteric atoms/groups, for example, NH2, F, OCH3, or deoxygenation at this position led to complete loss of activity (two to three orders of magnitude less cytotoxic).It was then deduced that 2 -OH may get involved in hydrogen bonding to the receptor, which was confirmed later by x-ray crystallography of docetaxel and its receptor mbulin complex. 

The structure of a catechol itself can be replaced by analogous heterocycles in various derivatives. All these compounds share the ability to chelate metal atoms and to form hydrogen-bonded second rings, the benzimidazole imitates this by way of a covalent ring structure.182 A successful bioisosteric replacement of a phenol or a catechol moiety is the 2-aminothiazolyl moiety. Active dopaminergic compounds which possess such a moiety are B-HT 920 (32)183 and pramipexole (19).146,154,155... 

Fig. 2.38. Bioisosteric replacement of m-OH of isoproterenol with a sulfonamide group and similar hydrogen-bonding capacity to a possible drug receptor.

Phosphinic acids are probably, with the phosphonic acids, the simplest phosphate bioisosteres [8]. Because of their tetrahedral geometry, phosphinic acids remain quite similar in shape and are approximately isosteric with phosphates. The main difference is the presence of two phosphorus-carbon bonds (phosphinic acids) or one phosphorus-carbon bond and a phosphoms-hydrogen bond (/f-phosphinic acids). One intrinsic character of the P-C bond is its chemical and enzymatic stability when compared to P-O or P-N bonds [9]. As a consequence, phosphinates (as well as phosphonates) are often used when hydrolysis becomes a bottleneck for the activity. The number of acidic functions but also pA a values are different between phosphate and phosphinic acids [10-12]. Indeed, the replacement of oxygen atoms by hydrogens in hypophosphorous acid slightly changed the pAa when compared to the first acidity of phosphoric acid (Fig. 1). However, the presence of an alkyl group directly bonded to the phosphoms results in an increase... 

Initial replacements of the amide functional group with other bioisosteres such as sulfonamide, ester, amine, and retro-amide lost the potency. This exercise confumed the importance of the hydrogen bonding between the carbonyl group (mostly as tautomer 2 ) on quinolinone with the amide carbonyl group. The fruit of this SAR yielded indole 5 (ECso = 9 nM), which was 10-fold more potent than indole 4. 

If bond breaking occurs during the rate-determining step of the reaction, then the overall reaction will be slowed by the replacement of hydrogen with deuterium. This is an example of a kinetic isotope effect. The use of deuterium as a bioisostere to manipulate rates of metabolism is a fairly new idea in drug discovery. If SD-254 successfully reaches the market, additional deuterated drugs will almost certainly be advanced into clinical trials. 

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