kinetic

LC kinetic stabilizer-1 is a potent, selective kinetic stabilizer for amyloidogenic immunoglobulin light chains, demonstrating EC50 values of 140 nM for WIL-FL* and 74.1 nM for WIL-FL*T46L/F49Y, respectively. Notably, WIL-FL represents an amyloidogenic FL LC dimer.

LC Kinetic Stabilizer-2 is a powerful stabilizer for amyloidogenic immunoglobulin light chains (LC), demonstrating significant efficacy with an EC50 of 24 nM.

Adipokinetic Hormone (Apis mellifera ligustica, Bombyx mori, Heliothis zea, Manduca sexta), a peptide shared by diverse insects, elicits a potent adipokinetic/hypertrehalosemic response. Despite this, it lacks the function to mobilize glycogen and an adequate glycogen reserve in the fat body for effective utilization [1].

Adipokinetic Hormone (AKH) (24-32), locust (TFA), a neurohormone extracted from the corpora cardiaca of locusts, serves to regulate lipid utilization during flight [1].

Adipokinetic hormone Gryllus bimaculatus (Grybi-AKH), an adipokinetic hormone, mobilizes lipids and carbohydrates from the insect fat body, effectively regulating energy homeostasis. It also enhances the locomotor activity of the two-spotted cricket and has potential applications in human medical studies for body weight regulation, weight loss induction, and the alleviation of glycogen storage disorders [1] [2] [3].

AG-10 (Acoramidis) is an orally active and selective kinetic stabilizer of TTR (transthyretin). AG-10 exhibits activity for WT and V122I-TTR. AG-10 is used in the study of transthyretin amyloidosis.

5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) is a synthetic compound. It has been used as a catalyst and as a tool in enzyme kinetic studies; it has also been used in studies of enzyme inhibition, as well as in drug receptor interaction studies.

TMC647055 Choline Hydroxide Salt is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase which potentially for the treatment of HCV infection. It has nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(

Adipokinetic hormone I (Locusta migratoria) (Lom-AKH-I), an insect adipokinetic hormone (AKH), increases fat body cAMP levels in vitro. AKHs regulate the mobilization of carbohydrates and lipids from fat body stores for flight, through AKH receptor(s)' association with cAMP production and glycogen phosphorylase activation via the stimulatory guanine nucleotide-binding protein (Gs) [1] [3].

Adipokinetic Hormone (AKH) (24-32), locust is a peptide hormone isolated from locusts.

Prokineticin 2 Isoform 2 (human), a hypothalamic neuropeptide, regulates thermoregulation and energy metabolism while decreasing food intake in rodents. This isoform is implicated in the study of metabolic syndrome (MetS), obesity, and hyperglycemia [1].

Adipokinetic hormone II (Locusta migratoria) (Lom-AKH-II), an insect adipokinetic hormone (AKH), elevates fat body cAMP levels in vitro. These hormones (AKHs) regulate the mobilization of carbohydrates and lipids from fat body reserves for flight, by activating AKH receptor(s) that stimulate cAMP production and glycogen phosphorylase through the stimulatory guanine nucleotide-binding protein (Gs) [1] [3].

Ensartinib (X-396) is a potent and dual ALK/MET inhibitor with IC50s of <0.4 nM and 0.74 nM, respectively. The ability of Ensartinib (X-396) to inhibit the growth of different cancer cell lines harboring ALK fusions or point mutations is tested. Ensartinib is potent in H3122 lung cancer cells harboring EML4-ALK E13;A20 (IC50: 15nM). Ensartinib is also potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC50: 45 nM). Furthermore, X-376 is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC50: 9 nM). X-376 also inhibits SY5Y neuroblastoma cells harboring ALK F1174L, MKN-45 gastric carcinoma cells harboring MET dependent, HepG2 cells and PC-9 lung cancer cell lines harboring EGFR exon 19 del with IC50s of 68 nM, 156 nM, 9.644 μM and 2.989 μM, respectively[1]. The effects of Ensartinib (X-396) in vivo against H3122 xenografts are examined. A pharmacokinetic study reveals that Ensartinib shows substantial bioavailability and moderate half-lives in vivo. Nude mice harboring H3122 xenografts are treated with Ensartinib at 25mg/kg bid. Ensartinib significantly delays the growth of tumors compared to vehicle alone. In the xenograft experiments, Ensartinib appears well-tolerated in vivo. Mouse weight is unaffected by Ensartinib treatment. Drug-treated mice appear healthy and do not display any signs of compound related toxicity. To further assess potential side effects of Ensartinib, additional systemic toxicity and toxico-kinetic studies are performed in Sprague Dawley (SD) rats. Following 10 days of repeated oral administration of Ensartinib at 20, 40, 80 mg/kg in SD rats, all animals survive to study termination. The no significant toxicity (NST) levels are determined to be 80mg/kg for Ensartinib. At NST levels, Ensartinib achieves an AUC of 66 μM×hr and a Cmax of 7.19 μM[1]. [1]. Lovly CM, et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinaseinhibitors. Cancer Res. 2011 Jul 15;71(14):4920-31.

1. Corylifol A (Corylinin) displays cytotoxic activity against HepG2 and Hep3B hepatocellular carcinoma cell lines, with IC50 values of 4.6 and 13.5 ug/ml, respectively. 2. Corylifol A and Biochanin A can be the potential uncouplers of neuronal nitric oxide synthase-postsynaptic density protein-95. 3. Corylifol A and bavachin are strong inhibitors of UDP-glucuronosyltransferase 1A1 (UGT1A1) with the inhibition kinetic parameters (Ki) values lower than 1 uM.4. Corylifol A and bakuchiol are naturally occurring potent inhibitors of hCE2, with low Ki values ranging from 0.62uM to 3.89 uM. 5. Corylifol A shows an inhibitory effect on IL-6-induced STAT3 promoter activity in Hep3B cells with IC50 values of 0.81 ± 0.15 uμ, it also inhibits STAT3 phosphorylation induced by IL-6 in Hep3B cells, suggests that corylifol A has antiinflammatory activity.

Eribulin (B1939) is a nonpaclitaxel microtubule kinetic inhibitor with anticancer activity that inhibits polymerization of microtubule protein subunits by preventing lengthening and shortening of microtubules during cell division.Eribulin is used in the study of metastatic breast cancer and solid tumors.

α-D-Glucose-1-phosphate is an intermediate in glycogen metabolism.1,2It is a precursor in the biosynthesis of UDP-glucose, the glucose donor in glycogen biosynthesis.2α-D-Glucose-1-phosphate can be formed during glycogen breakdownviaphosphorolytic cleavage of glycogen by glycogen phosphorylase.1It can be converted to glucose-6-phosphate by phosphoglucomutase. α-D-Glucose-1-phosphate is combined with CTP by α-D-glucose-1-phosphate cytidylyltransferase to form CDP-glucose in the first step of CDP-D-tyvelose biosynthesis inS. typhi.3Bacterial sucrose phosphorylase converts sucrose and phosphate into D-fructose and α-D-glucose-1-phosphate.4 1.Berg, J.M., Tymoczko, J.L., and Stryer, L.Glycogen breakdown requires the interplay of several enzymesBiochemistry(2002) 2.Berg, J.M., Tymoczko, J.L., and Stryer, L.Glycogen is synthesized and degraded by different pathwaysBiochemistry(2002) 3.Koropatkin, N.M., and Holden, H.M.Molecular structure of ɑ-D-glucose-1-phosphate cytidylyltransferase from Salmonella typhiJ. Biol. Chem.279(42)44023-44029(2004) 4.Goedl, C., Schwarz, A., Minani, A., et al.Recombinant sucrose phosphorylase from Leuconostoc mesenteroides: Characterization, kinetic studies of transglucosylation, and application of immobilised enzyme for production of ɑ-Ｄ-glucose 1-phosphateJ. Biotechnol.129(1)77-86(2007)

Acoramidis hydrochloride (Alxn2060 hydrochloride) is an orally active and selective kinetic stabilizer of WT and V122I- TTR (transthyretin) . Acoramidis hydrochloride is used in the study for transthyretin amyloidosis.

α-Amylase/α-Glucosidase-IN-1 (compound 33) is an effective inhibitor of α-amylase/α-glucosidase with IC 50 s of 2.01, 2.09 μM for α-amylase and α-glucosidase, respectively. Kinetic studies predict that α-Amylase/α-Glucosidase-IN-1 has the potential of anti hyperglycemia [1].

RO-5328673 is a dual NK2/NK3 antagonist. O5328673. [(3)H]RO5328673 bound to a single saturable site on hNK2, hNK3 and gpNK3 with high-affinity. RO5328673 acted as an insurmountable antagonist at both human and guinea-pig NK3 receptors in the [(3)H]IP accumulation assay. In binding kinetic analyses, [(3)H]RO5328673 had fast association and dissociation rates at hNK2 while it had a fast association rate and a remarkably slow dissociation rate at gp and hNK3. In electrophysiological recordings of gp SNpc, RO5328673 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurons with an insurmountable mechanism of action. RO5328673 exhibited in-vivo activity in gerbils, robustly reversing the senktide-induced locomotor activity.

Adenosine 3',5'-diphosphate sodium salt is an inhibitor of hydroxysteroid sulfotransferases, which are adenine nucleotides containing a phosphate group at the 3' and 5' positions of the pentose ribose.Adenosine 3',5'-diphosphate (sodium salt) is the product of 3'-phosphoadenosine 5'-phosphosulfonate (PAPS), a cofactor of sulfotransferases (SULTs). diphosphate disodium is the product of 3'-phosphoadenosine 5'-phosphosulfonate (PAPS), a cofactor for sulfotransferases (SULTs), which has been used to study the kinetic properties and structure of SULTs.

Diisopropyl tartrate is a reagent for kinetic resolution of racemic allylic alcohols and α-furfuryl amides. It acts by enantioselective epoxidation.

Sulfamonomethoxine sodium is a long-acting sulfonamide antibacterial agent utilized in blood kinetic studies; it inhibits dihydropteroate synthetase, thereby blocking folic acid synthesis [1].

CBS-3595 is a potent and dual Inhibitor of p38α MAPK/PDE-4 with a superior profile regarding its anti-inflammatory effects. CBS-3595 features moderate inhibition of p38α MAPK and PDE-4 in the higher nanomolar range in combination with excellent kinetic pr

OK-1035 is a potent and selective DNA-PK inhibitor. When a synthetic peptide was used as a substrate, OK-1035 caused 50% inhibition of DNA-PK activity at 8 microM. OK-1035 inhibited the phosphorylation by DNA-PK of consensus peptide as well as that of recombinant human wild type-p53. Kinetic studies indicated that OK-1035 inhibited DNA-PK activity in an ATP-competitive manner.

Rp-cAMPS sodium salt, a cAMP analog, is a potent, competitive cAMP-induced activation of cAMP-dependent PKA I and II (Kis of 12.5 μM and 4.5 μM, respectively) antagonist. Rp-cAMPS sodium salt is resistant to hydrolysis by phosphodiesterases[1][2][3][4][5][6]. A membrane-permeable competitive cAMP antagonist (Rp-cAMPS) that blocks PKA activation by binding to the regulatory subunits without dissociating the kinase holoenzyme also inhibits synaptic plasticity but has no effect on normal synaptic transmission[2]. Rp-cAMPS (10 μM, 15 min) decreases the monosynaptic EPSCs evoked at the PB-CeLC and BLA-CeLC synapses in slices from arthritic rats but not in control neurons from normal animals. The inhibitory effect of Rp-cAMPS is significant compared to predrug (ACSF) control values obtained in the same neurons[2]. [1]. R J de Wit, et al. Inhibitory action of certain cyclophosphate derivatives of cAMP on cAMP-dependent protein kinases. Eur J Biochem. 1984 Jul 16;142(2):255-60. [2]. Rothermel JD, et al. A mechanistic and kinetic analysis of the interactions of the diastereoisomers of adenosine 3’,5’-(cyclic)phosphorothioate with purified cyclic AMP-dependent protein kinase. Biochem J. 1988 May 1;251(3):757-62.[3]. Fu Y, et al. PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior. Mol Pain. 2008 Jul 16;4:26.[4]. Kuriyama S, et al. Isoproterenol inhibits rod outer segment phagocytosis by both cAMP-dependent and independent pathways. Invest Ophthalmol Vis Sci. 1995 Mar;36(3):730-6.[5]. Dostmann WR, et al. Probing the cyclic nucleotide binding sites of cAMP-dependent protein kinases I and II with analogs of adenosine 3’,5’-cyclic phosphorothioates. J Biol Chem. 1990 Jun 25;265(18):10484-91.[6]. Van Haastert PJ, et al. Competitive cAMP antagonists for cAMP-receptor proteins. J Biol Chem. 1984 Aug 25;259(16):10020-4.

Tafamidis-d3 is a deuterated compound of Tafamidis. Tafamidis has a CAS number of 594839-88-0. Tafamidis is a kinetic stabilizer of transthyretin (TTR) that prevents amyloidogenesis by wild-type and mutant TTRs. It binds to TTR with negative cooperativity (Kd1: 3 nM; Kd2: 278 nM) to stabilize the TTR dimer-dimer interface and inhibit tetrameric dissociation. Tafamidis stabilizes wild-type and clinically significant V30M and V122I mutant TTR amyloidogenic homotetramers (EC50s: 2.7-3.2 μM) under fibril-promoting, denaturing, and physiological conditions in vitro. It stabilizes TTR heterotetramers containing wild-type and mutant subunits ex vivo in human plasma derived from patients carrying V30M or V1221 mutations when used at a concentration of 7.2 μM. Formulations containing tafamidis have been used for the treatment of familial amyloid polyneuropathy.

Tafamidis (Fx-1006A) is a kinetic stabilizer of transthyretin (TTR) that prevents amyloidogenesis by wild-type and mutant TTRs. It binds to TTR with negative cooperativity (Kd1: 3 nM; Kd2: 278 nM) to stabilize the TTR dimer-dimer interface and inhibit tetrameric dissociation. Tafamidis stabilizes wild-type and clinically significant V30M and V122I mutant TTR amyloidogenic homotetramers (EC50s: 2.7-3.2 μM) under fibril-promoting, denaturing, and physiological conditions in vitro. It stabilizes TTR heterotetramers containing wild-type and mutant subunits ex vivo in human plasma derived from patients carrying V30M or V1221 mutations when used at a concentration of 7.2 μM. Formulations containing tafamidis have been used for the treatment of familial amyloid polyneuropathy.

(E)-Ajoene is a disulfide that has been found inA. sativumand has diverse biological activities.1,2,3,4It is active against Gram-positive and Gram-negative bacteria (MICs = 10-250 and 150->500 μg/ml, respectively) and fungi (MICs = 15-50 μg/ml).1(E)-Ajoene inhibits proliferation of a variety of cancer cells, including MDA-MB-231 breast, HeLa cervical, and WHCO1 esophageal cancer cells (IC50s = 18.6, 61, and 39.2 μM, respectively).2It also inhibits human glutathione reductase andT. cruzitrypanothione reductase when used at a concentration of 200 μM.3(E)-Ajoene (25 mg/kg) is neuroprotective in a gerbil model of ischemia-reperfusion injury, reducing reactive astrocytosis and microgliosis in the hippocampal CA1 region.4 1.Yoshida, H., Iwata, N., Katsuzaki, H., et al.Antimicrobial activity of a compound isolated from an oil-macerated garlic extractBiosci. Biotechnol. Biochem.62(5)1014-1017(1998) 2.Kaschula, C.H., Hunter, R., Hassan, H.T., et al.Anti-proliferation activity of synthetic ajoene analogues on cancer cell-linesAnticancer Agents Med. Chem.11(3)260-266(2011) 3.Gallwitz, H., Bonse, S., Martinez-Cruz, A., et al.Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: Crystallographic, kinetic, and spectroscopic studiesJ. Med. Chem.42(3)364-372(1999) 4.Yoo, D.Y., Kim, W., Nam, S.M., et al.Neuroprotective effects of Z-ajoene, an organosulfur compound derived from oil-macerated garlic, in the gerbil hippocampal CA1 region after transient forebrain ischemiaFood Chem. Toxicol.721-7(2014)

PD-85639 is a voltage-gated sodium (Na+) channel blocker (75% in 10 min & >95% in 25 min blockage of Na+ current by 25 μM PD85,639; whole-cell patch clamp using primary rat brain neurons) that is shown to target rat brain Nav1.2 with simultaneous high- and low-affinity modes of binding (EC50 = 56 nM/40% & 20 μM/60% at pH 9.0, 5 nM/28% & 3 μM/72% at pH 7.4, against 2 nM [3H]-PD85,639 for binding rat brain synaptosomes; EC50 = 17 nM/39% & 10 μM/61% using at pH 9.0 using rat brain synaptosome membranes) and a fast kinetic (t1/2 = 1.2 at 4°C, <0.5 min at 25°C), competitive against the local anesthetic Na+ channel blockers tetracaine, bupivacaine, and mepivacaine, as well as Na+ channel activators veratridine and batrachotoxin (K1 = 0.26 μM against 5 nM [3H]-BTX for binding rat neocrotical membranes).

Sulfamonomethoxine is a long-acting sulfonamide antibacterial agent, blocks the synthesis of folic acid by inhibiting synthetase of dihydropteroate.

AM-9514 is a novel, potent Glucokinase (GK) activator. AM-9514 showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model. Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis.

Coumarin-quinone conjugate is a fluorescent substrate for NADH:ubiquinone oxidoreductases.1It is comprised of a coumarin fluorophore conjugated to a ubiquinone analog that can be reduced by NADH:ubiquinone oxidoreductases. It has been used to measure the kinetic parameters of apoptosis-inducing factor mitochondria-associated 2/ferroptosis suppressor protein 1 (AIFM2/FSP1). 1.Doll, S., Freitas, F.P., Shah, R., et al.FSP1 is a glutathione-independent ferroptosis suppressorNature575(7784)693-698(2019)

Sulfamonomethoxine D4 is a deuterium labeled Sulfamonomethoxine. Sulfamonomethoxine is an agent of long acting sulfonamide antibacterial, used in blood kinetic studies,and blocks the synthesis of folic acid by inhibiting synthetase of dihydropteroate.

Tafamidis meglumine (Fx-1006A) is a Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade

Tiotropium Bromide hydrate (BA-679 BR hydrate) is a potent anticholinergic and bronchodilator, serving as a muscarinic receptor antagonist, specifically targeting mAChR. It is developed for treating chronic obstructive airways disease (COPD), demonstrating novel and long-lasting effects. Binding studies with [3H]tiotropium bromide in human lung reveal its high potency and equivalent affinity for M1-, M2-, and M3-receptors, making it roughly 10 times more effective than ipratropium bromide. It notably inhibits cholinergic nerve-induced contraction of both guinea-pig and human airways more potently than atropine or ipratropium bromide, albeit with a slower onset. Tiotropium bromide uniquely presents slow dissociation from M3-receptors on airway smooth muscle and rapid dissociation from M2 autoreceptors on cholinergic nerve terminals. As a quaternary ammonium derivative, it shows high affinity and special kinetic selectivity towards muscarinic receptors across M1-, M2-, and M3-subtypes, due to its slower dissociation from M1- and M3-receptors compared to M2-receptors.