liver microsomes

Adagrasib (MRTX849) is an orally active and selective covalent inhibitor of KRAS G12C. Adagrasib binds to the GDP state of the inactive conformation of KRAS G12C and inhibits KRAS and its downstream signaling. Adagrasib exhibits inhibitory activity against KRAS G12C mutant tumors.

(S)-Lisofylline is the inactive optical enantiomer of (R)-lisofylline which is an anti-inflammatory agent. (S)-Lisofylline is exclusively converted to pentoxifylline in human liver microsomes.

Pilocarpine Hydrochloride (NSC 5746 HCl) , a nonselective muscarinic acetylcholine receptor agonist, is utilized to produce an experimental model of epilepsy.

Clomethiazole (Distraneurin) is an orally active GABAA agonist and it is an anticonvulsant agent. It also has the potential for treating convulsive status epilepticus. Chlormethiazole inhibits cytochrome P450 isoforms: CYP2A6 and CYP2E1 in human liver microsomes.

Phoxim is an organophosphate insecticide that inhibits acetylcholinesterase (AchE) activity in the nervous system of insects. It is used in veterinary medicine for the treatment of ectoparasitic mites. It is toxic to aquatic organisms and may affect cytochrome P450 enzyme (CYP1A) activity and its expression levels in fish liver microsomes. In addition, sub-lethal doses of phoxim affected detoxification enzyme activities of adult mulberry whitefly, such as changes in the activities of glutathione S-transferase (GST), carboxylesterase (CarE) and acetylcholinesterase (AchE).

1-Phenylpyrrole (NSC-16581) is an inhibitor of CYP450 dependant monooxygenase activity in microsomes from rat liver.

LY 43578 is an orally active aromatase inhibitor. LY43578 could inhibit O-demethylation of P-450-dependent p-nitroanisole and N-demethylation of ethylmorphine (IC50 of 0.3 and 5 μm, respectively) in rat liver microsomes. LY 43578 can be used to study neurological and cardiovascular diseases.

Ezutromid (BMN 195) is a translation modulator of Small utrophin (EC50: 0.4 uM). Ezutromid is an orally bioavailable small molecule that transcriptionally upregulates the utrophin gene, increasing both utrophin mRNA and protein. Through this action, Ezutromid increases muscle function in dystrophin-deficient MDX mice, a mouse model of muscular dystrophy.

CYP1B1-IN-4, a 2,4-diarylthiazole compound, exhibits selective inhibition of CYP1B1 (IC50=0.2 nM), demonstrating minimal cytotoxicity and high stability in human and rat liver microsomes [1].

Enniatin A1, a cyclic hexadepsipeptide composed of alternating D-α-hydroxyisovaleric acids and N-methyl-L-amino acids isolated from Fusarium mycotoxins, exhibits anticarcinogenic effects through the induction of apoptosis and disruption of the ERK signaling pathway. It also inhibits ACAT in rat liver microsomes with an IC50 of 49 μM.

Thalifendine is one of the main products of Berberine demethylation catalyzed by CYP51 (secreted by intestinal flora), which has anti-inflammatory effects, reduces intestinal inflammation, improves intestinal barrier function, and reduces the production of inflammatory factors.

YM17E is an inhibitor of ACAT with IC50 of 44 nM in rabbit liver microsomes in vitro.

Cevimeline hydrochloride hemihydrate ((-)-SNI-2011), a novel muscarinic receptor agonist, is being explored as a potential treatment for xerostomia in Sjogren's syndrome, exhibiting an IC50 value indicative of its affinity for mAChR. This compound's pharmacological effects on the gastrointestinal, urinary, and reproductive systems, alongside its impact on various tissues, were thoroughly examined in species including mice, rats, guinea pigs, rabbits, and dogs. The metabolic breakdown of (-)-SNI-2011 was studied in vitro using rat and dog liver microsomes to assess its biotransformation. Upon oral administration, peak plasma concentrations were reached within an hour in both rats and dogs, showcasing rapid absorption and a subsequent decrease in concentration with a half-life ranging from 0.4 to 1.1 hours. Bioavailability was noted at 50% in rats and 30% in dogs. Metabolic pathways highlighted significant species differences, with both S- and N-oxidized metabolites identified in rats, but only N-oxidized metabolites in dogs. Additionally, gender differences in pharmacokinetics were observed in rats but were absent in dogs. In vitro studies pinpointed the involvement of cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) in the metabolism of (-)-SNI-2011, specifically through sulfoxidation and N-oxidation processes, respectively. CYP2D and CYP3A were identified as the primary enzymes responsible for sulfoxidation in rat liver microsomes.

(+)-Cevimeline hydrochloride hemihydrate ((+)-SNI-2011), a potent muscarinic receptor agonist, shows promise as a therapeutic candidate for xerostomia in Sjogren's syndrome. It exhibits a broad pharmacological profile across various systems in animal models including mice, rats, guinea pigs, rabbits, and dogs. Metabolism studies using rat and dog liver microsomes reveal rapid absorption with peak plasma concentrations (Cmax) within one hour post-oral administration and a half-life (t1 2) between 0.4 to 1.1 hours. Bioavailability is 50% in rats and 30% in dogs. Metabolic analysis shows species-specific differences: rats produce S- and N-oxidized metabolites, while dogs produce only N-oxidized metabolites. Sex-based pharmacokinetic differences were noted in rats but not in dogs. In vitro studies indicate cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) involvement in the sulfoxidation and N-oxidation of SNI-2011, with CYP2D and CYP3A mainly responsible for sulfoxidation in rat liver microsomes.

DMEA-PNU-159682 (molecule D12) is an ADC cytotoxin molecule that includes neomycin (MMDX) metabolites from liver microsomes and the effective ADC cytotoxin PNU-159682.

Enniatin A, a Fusarium mycotoxin, inhibits acyl-CoA: cholesterol acyltransferase (ACAT) with an IC50 of 22 μM in rat liver microsome enzyme assays.

Enniatins B decreases the activation of ERK (p44 p42). Enniatin B is a Fusarium mycotoxin. Enniatin B inhibits acyl-CoA: cholesterol acyltransferase (ACAT) activity with an IC50 of 113 μM in an enzyme assay using rat liver microsomes.

Enniatin B1, a Fusarium mycotoxin, crosses the blood-brain barrier, decreases the activation of ERK (p44 p42), and inhibits moderately TNF-α-induced NF-κB activation. Furthermore, it inhibits acyl-CoA: cholesterol acyltransferase (ACAT) activity, exhibiting an IC50 of 73 μM in rat liver microsome enzyme assays.

Dagrocorat is a novel and dissociated agonist of glucocorticoid receptor.

DBCO-PEG4-VC-PAB-DMEA-PNU-159682, a drug-linker conjugate for antibody-drug conjugates (ADC), comprises the ADC linker DBCO-PEG4-VC-PAB and the potent ADC cytotoxin DMEA-PNU-159682, which includes metabolites of nemorubicin (MMDX) from liver microsomes and the ADC cytotoxin PNU-159682[1].

Mal-PEG4-VC-PAB-DMEA-PNU-159682 is a drug-linker conjugate designed for antibody-drug conjugate (ADC) therapy. It combines the ADC linker, Mal-PEG4-VC-PAB, with the potent ADC cytotoxin, DMEA-PNU-159682. The cytotoxin, DMEA-PNU-159682, is derived from metabolites of nemorubicin (MMDX) found in liver microsomes, as well as the ADC cytotoxin PNU-159682 [1].

Mal-Phe-C4-VC-PAB-DMEA-PNU-159682 is a drug-linker conjugate utilized in antibody-drug conjugate (ADC) therapy. It comprises the ADC linker Mal-Phe-C4-VC-PAB and the potent ADC cytotoxin DMEA-PNU-159682, which encompasses metabolites of nemorubicin (MMDX) derived from liver microsomes, as well as the ADC cytotoxin PNU-159682 [1].

Pradefovir mesylate (Hepavir B) is converted to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in human liver microsomes with Km of 60 μM.

HIV-1inhibitor-75 is a human immunodeficiency virus 1 (HIV-1) inhibitor with an EC50 range of 0.0039-0.338 μM. Its target is the reverse transcriptase, exhibiting an IC50 value of 0.055 μM. Additionally, HIV-1inhibitor-75 demonstrates good metabolic stability in vitro, presenting moderate clearance rates and an extended half-life in human plasma and liver microsomes.