Pyridostigmine is hydrolyzed by cholinesterases systemically, including in the blood, and by microsomal enzymes in the liver, though this remains poorly defined. The primary hydrolysis product is 3-hydroxy-N-methyl-pyridinium (HNM), which can be glucuronidated. One study suggested the existence of as many as eight metabolites in the urine of patients receiving radiolabeled pyridostigmine intravenously, including various glucuronidated, demethylated, and oxidized (quinone) metabolites. Another study confirmed that HNM is the main metabolite, and suggested additional possible metabolites such as a 3,4- or 3,6-dihydroxy-N-methyl-pyridinium or a methoxy- or acetoxy-N-methyl-pyridinium. The exact products formed, apart from HNM, require further validation.
Pyridostigmine is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Pyridostigmine administered orally is poorly absorbed in the GI tract, with an oral bioavailability of only 10-20%. However, this may in part be due to some metabolism by both the blood and liver. Approximately 1-2 hours following a single oral dose of 60 mg, the Cmax was determined to be 40-60 μg/L. Pyridostigmine follows approximately linear kinetics, with a direct correlation between the dose and plasma AUC. Pyridostigmine taken orally with food results in a flatter peak to the plasma concentration vs. time curve. The peak plasma concentrations are reached ~90 minutes later than in fasted subjects but with no change in bioavailability or AUC.
Pyridostigmine is primarily renally eliminated. Roughly 90% of an intravenous dose is recovered in the urine within 24 hours, with unchanged pyridostigmine and its main metabolite HNM recovered in an approximately 4:1 ratio.
Pyridostigmine administered intravenously in healthy, myasthenic, and surgical patients has a range of distribution volumes, between 0.53 and 1.76 L/kg.
Pyridostigmine administered intravenously in healthy, myasthenic, and surgical patients has a range of clearance values, between 0.29 and 1.0 L/h/kg.
来源:DrugBank
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2933399090
文献信息
[EN] SUBSTITUTED BENZYLAMINE COMPOUNDS, THEIR USE IN MEDICINE, AND IN PARTICULAR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION<br/>[FR] COMPOSÉS DE BENZYLAMINE SUBSTITUÉS, LEUR UTILISATION EN MÉDECINE, EN PARTICULIER DANS LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HÉPATITE C (VHC)
申请人：ASTEX THERAPEUTICS LTD
公开号：WO2013064538A1
公开（公告）日：2013-05-10
The invention provides compounds of the formula (I): or a salt, N-oxide or tautomer thereof, wherein A is CH, CF or nitrogen; E is CH, CF or nitrogen; and R0 is hydrogen or C1-2 alkyl; R1a is selected from CONH2; CO2H; an optionally substituted acyclic C1-8 hydrocarbon group; and an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S; R2 is selected from hydrogen and a group R2a; R2a is selected from an optionally substituted acyclic d-8 hydrocarbon group; an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1 or 2 ring members are heteroatom ring members selected from O, N and S; and an optionally substituted bicyclic heterocyclic group of 9 or 10 ring members, of which 1 or 2 ring members are nitrogen atoms; wherein at least one of R1 and R2 is other than hydrogen; R3 is an optionally substituted 3- to 10-membered monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatom ring members selected from N, O and S; R4a is selected from halogen; cyano; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy-C1-4 alkyl; and C1-2 alkoxy-C1-4 alkyl; R5 is selected from hydrogen and a substituent R5a; and R5a is selected from C1-2 alkyl optionally substituted with one or more fluorine atoms; C1-3 alkoxy optionally substituted with one or more fluorine atoms; halogen; cyclopropyl; cyano; and amino, The compounds have activity against hepatitis C virus and can be used in the prevention or treatment of hepatitis C viral infections.
TGR5 agonists of structural formula VIII(Q), wherein X, R1, R2, and R5 are defined in the specification, pharmaceutically acceptable salts thereof, compositions thereof, and use of the compounds and compositions for treating diseases. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases.
Certain pyrazoline derivatives with kinase inhibitory activity
申请人：Adams Ruth S.
公开号：US20080171754A1
公开（公告）日：2008-07-17
The present invention provides certain pyrazoline compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutical compositions and methods of using the compositions in the treatment of various diseases.
Benzoxazinyl-amidocyclopentyl-heterocyclic modulators of chemokine receptors
申请人：Goble D. Stephen
公开号：US20070238723A1
公开（公告）日：2007-10-11
Cyclopentyl compounds linked to a benzoxazinyl group through an amido moiety utilizing the ring nitrogen of the benzoxazine, and further substituted with a heterocyclic moiety, such compounds represented by formula I:
which are used to modulate the CCR-2 chemokine receptor to prevent or treat inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis; and pharmaceutical compositions comprising these compounds and the use of these compounds and compositions.
The present invention discloses a novel thyroid like compounds of formula (I), wherein R
1
R
2
, R
3
, R
4
and Z are as defined in the specification, method for its preparation, composition containing such compounds and use of such compounds and composition as medicament. Further, compounds of formula (I) has significantly low binding affinity to thyroid receptors and thus considerably devoid of thyrotoxic effects. The invention also relates to the use of the compound of formula (I) for the preparation of a medicament for treating various disease conditions such as obesity, dyslipidemia, metabolic syndrome and co-morbidities associated with metabolic syndrome.
