Chemistry and Pharmacology of CNS Depressants Related to 4-(4-Hydroxy-4-phenylpiperidino)butyrophenone Part I--Synthesis and screening data in mice

Janßen, Paul; Westeringh, C. van de; Jageneau, A; Demoen, Paul J. A.; Hermans, Bert; Daele, G H Van; Schellekens, K H; Eycken, C A Van Der

doi:10.1021/jm50004a007

Cited by 149 publications

(42 citation statements)

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“…Haloperidol (1 a) has remained one of the most widely used antipsychotics for the treatment of neuropsychiatric disorders such as schizophrenia since its development in the late 1950s, [1] due mainly to its efficacy in alleviating the positive symptoms (e.g. hallucination and delusion) of such diseases.…”

Section: Introductionmentioning

confidence: 99%

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

et al. 2008

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Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.

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Section: Introductionmentioning

confidence: 99%

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

et al. 2008

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“…Commercial HAL (Sigma) was recrystallized from diethyl ether/CHCl3, 4:1 (vol/vol), and the recrystallized material was shown to be pure by its melting point (mp 148.2-1490C; lit. 148.0-149.40C) (29), by NMR, and by elemental analysis. The purified material was used for all biological work even though little difference was found between the recrystallized and commercial samples.…”

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confidence: 99%

Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.

DesJarlais

Seibel

Kuntz

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

237

105

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By using a structure-based computer-assisted search, we have found a butyrophenone derivative that is a selective inhibitor of the human immunodeficiency virus 1 (HIV-1) protease. The computer program creates a negative image of the active site cavity using the crystal structure of the HIV-1 protease. This image was compared for steric complementarity with 10,000 molecules of the Cambridge Crystallographic Database. One of the most interesting candidates identified was bromperidol. Haloperidol, a closely related compound and known antipsychotic agent, was chosen for testing. Haloperidol inhibits the HIV-1 and HIV-2 proteases in a concentration-dependent fashion with a K1 of -100 ILM. It is highly selective, having little inhibitory effect on pepsin activity and no effect on renin at concentrations as high as 5 mM. The hydroxy derivative of haloperidol has a similar effect on HIV-1 protease but a lower potency against the HIV-2 enzyme. Both haloperidol and its hydroxy derivative showed activity against maturation of viral polypeptides in a cell assay system. Although this discovery holds promise for the generation of nonpeptide protease inhibitors, we caution that the serum concentrations of haloperidol in normal use as an antipsychotic agent are <10 ng/ml (0.03 IAM). Thus, concentrations required to inhibit the HIV-1 protease are >1000 times higher than the concentrations normally used. Haloperidol is highly toxic at elevated doses and can be life-threatening. Haloperidol is not useful as a treatment for AIDS but may be a useful lead compound for the development of an antiviral pharmaceutical.

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“…The sedative effect of an analgesic pethidine derivative (R1187) was reminiscent of the sedation produced by chlorpromazine and, after exploring hundreds of derivatives, haloperidol was discovered. Haloperidol was 50-100 times potent than chlorpromazine, with a better side-effect profile (Figure 2.9) [33].…”

Section: Aripiprazolementioning

confidence: 99%

Standalone Drugs

Proudfoot

2010

Analogue‐Based Drug Discovery II

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In volume I of Analogue-Based Drug Discovery we focused on analogue drugs with a double similarity, that is, those that are similar to another drug from both chemical and pharmacological viewpoints. These were referred to as structural and pharmacological analogues or, alternatively, full analogues. One special class of these analogues is considered to be direct analogues if they have identical pharmacophores -that is, they can be described by a general structure that includes most of the chemical skeleton. The book also discussed some examples of structural analogues, in which the similarity is limited to their chemical structures since they possess different pharmacological properties. We also proposed the term pharmacological analogues for drugs that have completely different chemical structures but similar pharmacological properties.Analogues are based on following a lead compound, and if this compound were a drug that opened up a new therapeutic treatment then we use the term pioneer drug. Such a drug is often referred to as first in class. One can subdivide pioneer drugs into those that have analogues and those that do not. Thus, the latter group provides a special subclass called standalone drugs,

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Chemistry and Pharmacology of CNS Depressants Related to 4-(4-Hydroxy-4-phenylpiperidino)butyrophenone Part I--Synthesis and screening data in mice

Cited by 149 publications

References 6 publications

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.

Standalone Drugs

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Chemistry and Pharmacology of CNS Depressants Related to 4-(4-Hydroxy-4-phenylpiperidino)butyrophenone Part I--Synthesis and screening data in mice

Cited by 149 publications

References 6 publications

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.

Standalone Drugs

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Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate