Lead bioisosterism

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

Andersen, K. E., Sprensen, J. L Huusfeldt, P. 0., Knutsen, L. J., Lau, J., Lundt, B. F., et al. (1999) Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates../. Med. Chem. 42,4281 4291. 

Despite many clinical similarities, these agents differ in their absorption, dosing with other drugs, and duration of actions for example, quinapril has a of 3 hours whereas ramipril has a of 13-17 hours. The quest for ACE inhibitors devoid of the sulfhydryl group also led to the evaluation of phosphonate-containing inhibitors, on the basis of the notion that phosphinic acid is bioisosterically equivalent to sulfhydryl and carboxylate groups in terms of Zn " chelation. This lead to the development of fosinopril... 

The frequently observed bioisosteric relation of benzene and thiophene applies to the clonidine series as well. Reaction of the thiophenyl thiourea (85-1), in which the amine group is flanked by substituents as in the prototype, with methyl iodide and a base gives the corresponding methyl thioether (85-2). Treatment of that intermediate with ethylene diamine leads to the formation of an imidazoline ring and the antihypertensive agent, tiamenidine (85-3) [90], shown as its imino tautomer. 

Successful development of a drug, from choice of the lead structure through preparation and testing of derivatives and bioisosteres to selection of the clinical candidate, requires that properties be optimized for potency, selectivity and delivery. 

Peptide-like compounds raise the further significant issue of chirality control. When all the chiral fragments consist of natural amino acids, the chiral sources are natural amino acids themselves. However, when chiral non-natural amino acids are used as bioisosteres of amino acid residues to construct peptide mimetic compounds, the chirality needs to be constructed as efficiently as possible. Multi-step or low-yielding processes resulting from the necessity to control chirality often lead to the potential risk of large amounts of waste and a high environmental burden. 

Lead explosion where a lead or leads are followed up by an analoguing experiment designed to probe the neighboring (bioisosteric) property space with the intention of finding active analogues and detecting structure-activity trends. 

In the parlance of medicinal chemistry, bioisosteres are groups of atoms that might be expected to impart similar physical and chemical properties when substituted from one biologically active molecule to another. They are frequently employed to try to generate additional active molecules from a known active lead—occasionally they even work ... 

P.H. Olesen, The use of bioisosteric groups in lead optimization, Curr. Opin. Drug Disc. Dev. 4 (2001) 471-478. 

The concept of bioisosterism has been used to theoretically evaluate structural variation Organophosphorous Agrochemicals within the lead structures of synthetic or natural origin prior to and during the preparation Insecticides (Tables 17.3a,b). Oiganophorous of molecules of specified efficacy, safety, sta- insecticides bind to Acetylcholinesterase (AchE),... 

With these early successes in hand, a key question arising is that of whether RNA-targeted DCC yields compounds that can serve as relevant leads for further medicinal chemistry studies Our group is currently engaged in efforts to demonstrate that the answer to this question is in the affirmative. For example, building on the efforts with the HIV-1 FSS RNA detailed above, non-reducible analogs incorporating a hydrocarbon (olefin or saturated alkane) bioisostere for the disulfide... 

Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the hexahydrothianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[ ]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability. 

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