Imidazole moiety replacements in the 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) to improve cytochrome P450 profile

Velaparthi, Upender; Liu, Peiying; Balasubramanian, Balu; Carboni, Joan M.; Attar, Ricardo M.; Gottardis, Marco M.; Li, Aixin; Greer, Ann; Zoeckler, Mary; Wittman, Mark D.; Vyas, Dolatrai M.

doi:10.1016/j.bmcl.2007.03.048

Cited by 45 publications

(18 citation statements)

References 26 publications

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“…As per historical precedence for imidazole derivatives such as ketoconazoles, the CYP inhibition potential was attributed to the imidazole unit. [14,15]. In accordance, they made modifications at the imidazole moiety and compared their CYP liability, while retaining or improving the primary kinase activity.…”

Section: Imidazole Modificationsmentioning

confidence: 72%

Modulation of Cytochrome-P450 Inhibition (CYP) in Drug Discovery: A Medicinal Chemistry Perspective

Kumar¹,

Sharma²,

Roychowdhury

2012

CMC

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Cytochrome P450 (CYP450) has widely been implicated for drug-drug interactions (DDI) in the pharmaceutical industry. Inhibition or induction of this enzyme family has led to withdrawal of multiple drugs from the market leading to major time and financial losses for the pharmaceutical industry. CYP450 plays a prevailing role in the biotransformation of a large number of structurally diverse drugs. Few isoenzymes of the CYP enzyme family (CYP3A4, 2D6 and 2C9 family) are mainly involved in metabolism of most of the drugs. To avoid such interactions and potentially minimize DDI, major pharmaceutical organizations prefer to incorporate CYP enzyme screening at an early stage of their discovery program. While this has been a prevalent practice in the pharmaceutical industry lately, there is very limited literature available reviewing the relationship between chemotypes and CYP isoforms. This review will collate literature pertaining to CYP-inhibition modulation through physicochemical parameters and chemical modification and thus bring to focus commonly used trends by medicinal chemists world-wide.

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Section: Imidazole Modificationsmentioning

confidence: 72%

Modulation of Cytochrome-P450 Inhibition (CYP) in Drug Discovery: A Medicinal Chemistry Perspective

Kumar¹,

Sharma²,

Roychowdhury

2012

CMC

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“…33,34 Piperidone derivative 11b (IC 50 = 0.9 nM), 1,4-dioxa-8-azaspiro [4.5]decane derivative 11c (IC 50 = 1.3 nM) and the morpholine compound 11g (IC 50 = 0.9 nM) showed potent inhibition of PDE4 activity comparable to that of 11a, while piperidine derivative 11d and dimethylamino derivative 11f had somewhat lower potency (Table 2). A similar profile was observed for the TNF-a-suppressing activity.…”

Section: Biological Evaluationmentioning

confidence: 77%

Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors

Kagayama¹,

Morimoto²,

Nagata³

et al. 2009

Bioorganic & Medicinal Chemistry

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“…The pIC 50 of model drugs for integrase was set as the template to assist with model assessment [48]. Before creating the prediction model, the descriptors of these ligands were evaluated by the genetic approximation (GA) algorithm of the Calculate Molecular Properties module in Accelrys Discovery Studio 2.5 [49].…”

Section: Methodsmentioning

confidence: 99%

Lead Screening for HIV-1 Integrase (IN) Inhibited by Traditional Chinese Medicine

Hung

Chen

Chan

et al. 2014

BioMed Research International

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Human immunodeficiency virus causes the acquired immunodeficiency syndrome (AIDS) and becomes a serious world-wide problem because of this disease's rapid propagation and incurability. Integrase strand transfer inhibitors (INSTIs) supports HIV have rapid drug resistance for antitreatment. Screening the traditional Chinese medicine (TCM) database by simulating molecular docking and molecular dynamics may select molecular compounds to inhibit INSTIs against HIV drug resistance. (S)-cathinone and (1S,2S)-norpseudoephedrine are selected based on structure and ligand-based drugs are designed and then get higher bioactivity predicted score from SVM than Raltegravir and other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions and hydrogen bond variations define the main regions of important amino acids in integrase. In addition to the detection of TCM compound efficacy, we suggest (1S,2S)-norpseudoephedrine is better than the others based on the analysis of interaction and the effect on the structural variation.

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Imidazole moiety replacements in the 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) to improve cytochrome P450 profile

Cited by 45 publications

References 26 publications

Modulation of Cytochrome-P450 Inhibition (CYP) in Drug Discovery: A Medicinal Chemistry Perspective

Modulation of Cytochrome-P450 Inhibition (CYP) in Drug Discovery: A Medicinal Chemistry Perspective

Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors

Lead Screening for HIV-1 Integrase (IN) Inhibited by Traditional Chinese Medicine

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