Niaprazine is a histamine H1-receptor antagonist with marked sedative properties. Niaprazine has antihistamine and antiserotonin activities and can be used for sleep disorder research[1][2]. Niaprazine exhibits a low affinity for the vesicular monoamine transporter and for D2, α2, β, H1 and mAch receptors. Niaprazine, particularly the (+)stereoisomer, has a higher affinity for α1 (Ki = 77 nM) and 5-HT2 (Ki = 25 nM) binding sites, but is poorly recognized by 5-HT1A and 5-HT1B binding sites[2]. Niaprazine (60 mg/kg; i.p.; once) treatment increases rat brain 5-hydroxyindole acetic acid (5-HIAA) concentrations 30 min after treatment, and reduced them at 3-8 hr after treatment. Niaprazine also produces a short-lasting depletion of rat brain noradrenaline (NA) and dopamine (DA)[3]. Animal Model: Male Sprague-Dawley rats (150-200 g)[3] [1]. D Scherman, et al. Molecular pharmacology of niaprazine. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12(6):989-1001. [2]. P G Rossi, et al. Niaprazine in the treatment of autistic disorder. J Child Neurol. 1999 Aug;14(8):547-50. [3]. P E Keane, et al. The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain. Neuropharmacology. 1982 Feb;21(2):163-9.

RWJ-56110 dihydrochloride is a potent, selective, peptide-mimetic inhibitor of PAR-1 activation and internalization (binding IC50=0.44 uM) and shows no effect on PAR-2, PAR-3, or PAR-4. RWJ-56110 dihydrochloride inhibits the aggregation of human platelets induced by both SFLLRN-NH2 (IC50=0.16 μM) and thrombin (IC50=0.34 μM), quite selective relative to U46619 . RWJ-56110 dihydrochloride blocks angiogenesis and blocks the formation of new vessels in vivo. RWJ-56110 dihydrochloride induces cell apoptosis[1][2]. Proteinase-activated receptors (PARs) are a family of G protein-coupled receptors activated by the proteolytic cleavage of their N-terminal extracellular domain, exposing a new amino terminal sequence that functions as a tethered ligand to activate the receptors.RWJ56110 inhibits the aggregation of human platelets induced by both SFLLRN-NH2 (IC50=0.16 μM) and thrombin (IC50=0.34 μM) while being quite selective relative to collagen and the thromboxane mimetic U46619 [1].RWJ-56110 dihydrochloride is fully inhibits thrombin-induced RASMC proliferation with an IC50 value of 3.5 μM. RWJ-56110 dihydrochloride shows blockade of thrombin's action with RASMC calcium mobilization (IC50=0.12 μM), as well as with HMVEC (IC50=0.13 μM) and HASMC calcium mobilization (IC50=0.17 μM)[1].RWJ56110 (0.1-10 μM; 24-96 hours) inhibits endothelial cell growth dose-dependently, with half-maximal inhibitory concentration of RWJ56110 is approximately 10 μM[2].RWJ56110 (0.1-10 μM; 6 hours) inhibits DNA synthesis of endothelial cells in a thymidine incorporation assays. Endothelial cells are in fast-growing state (50-60% confluence), RWJ56110 inhibits cell DNA synthesis in a dose-dependent manner, but when cells that are in the quiescent state (100% confluent), the inhibitory effect of PAR-1 antagonists is much less pronounced[2].RWJ56110 (0.1-10 μM; pretreatment for 15 min) inhibits thrombin-induced Erk1/2 activation in a concentration-dependent manner. However, when endothelial cells are stimulated by FBS (final concentration 4%), it reduces partially the activated levels of Erk1/2[2].RWJ56110 (30 μM; 24 hours) has an inhibitory effect on endothelial cell cycle progression. It reduces the percentage of cells in the S phase, while alterations in the percentages of G1 and G2/M cells are less pronounced[2]. Western Blot Analysis[2] Cell Line: Endothelial cells [1]. Andrade-Gordon, et al.Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. oc Natl Acad Sci U S A. 1999 Oct 26;96(22):12257-62. [2]. Panagiota Zania, et al. Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis. J Pharmacol Exp Ther. 2006 Jul;318(1):246-54.

CK2-IN-9, a potent and selective CK2 kinase inhibitor, exhibits an inhibitory concentration (IC50) of 3 nM against its target enzyme and hampers Wnt reporter activity with an IC50 of 75 nM. In rats, it demonstrates low exposure (AUC=0.36 μM/h) and high clearance (CL=65 mL/min/kg) [1].

AZD1283 is an effective P2Y12 receptor antagonist (EC50: 3.0 ug/kg/min, binding IC50: 11 nM). AZD1283 dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED50 values of 3.0 and 10 μg/kg/min, respectively. The doses induced the increase in bleeding time at 33 and 100 μg/kg/min for 3- and 13-fold, respectively. Thus, the therapeutic index (TI) was ≥10 for both compounds.

PI3Kα-IN-4 is a potent, selective, and orally active PI3Kα inhibitor, demonstrating an IC50 of 1.8 nM and exhibiting antitumor activity[1].

A2AR-antagonist-1 (compound 38), an orally active adenosine A2A receptor antagonist with an IC50 value of 29 nM, demonstrates anti-tumor properties and stability in mouse liver microsomes (t1/2 = 86.1 min). Additionally, it activates T cells by inhibiting immunosuppressive molecules (LAG-3 and TIM-3) and promoting expression of effector molecules (GZMB, IFNG, and IL-2) [1].

Teneligliptin (MP-513) is a potent chemotype prolylthiazolidine-based DPP-4 inhibitor, which competitively inhibits human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC50s of approximately 1 nM. Teneligliptin (MP-513) inhibits all these DPP-4 enzymes in a concentration-dependent manner. The IC50s of Teneligliptin (MP-513) for rhDPP-4, human plasma, and rat plasma are 0.889, 1.75, and 1.35 nM, respectively. A study of enzyme inhibition kinetics is conducted for Teneligliptin (MP-513) using Gly-Pro-MCA as the substrate and rhDPP-4 as the enzyme source. Plots based on the Michaelis-Menten equation reveals that Teneligliptin (MP-513) inhibits DPP-4 in a substrate-competitivemanner; the residual sum of squares for competitive and non-competitive models is 0.162 and 0.192, respectively. Ki, Km, and Vmax values are 0.406 nM, 24 μM, and 6.06 nmol/min, respectively. Teneligliptin (MP-513) inhibits the degradation of GLP-1(7-36)amide with an IC50 of 2.92 nM[1]. Oral administration of Teneligliptin (MP-513) in Wistar rats results in the inhibition of plasma DPP-4 with an ED50 of 0.41 mg/kg. Plasma DPP-4 inhibition is sustained even at 24 h after administration of Teneligliptin (MP-513). An oral carbohydrate-loading test in Zucker fatty rats shows that Teneligliptin (MP-513) at ≥0.1 mg/kg increases the maximum increase in plasmaglucagon-like peptide-1 and insulin levels, and reduces glucose excursions. This effect is observed over 12 h after a dose of 1 mg/kg. An oral fat-loading test in Zucker fatty rats also shows that Teneligliptin (MP-513) at 1 mg/kg reduces triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of Teneligliptin (MP-513) for two weeks reduces glucose excursions in the oral carbohydrate-loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. Oral administration of Teneligliptin (MP-513) inhibits plasma DPP-4 in rats in a dose-dependent manner. The ED50 value for Teneligliptin (MP-513) is calculated to be 0.41 mg/kg, while those for Sitagliptin and Vildagliptin, 27.3 and 12.8 mg/kg, respectively[1]. Teneligliptin (MP-513) improves the histopathological appearance of the liver and decreases intrahepatic triglyceride levels in an NAFLD model mouse, which is associated with downregulation of hepatic lipogenesis-related genes due to AMPK activation[2]. [1]. Fukuda-Tsuru S, et al. A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur J Pharmacol. 2012 Dec 5;696(1-3):194-202. [2]. Ideta T, et al. The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice. Int J Mol Sci. 2015 Dec 8;16(12):29207-18.

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).

Piperazine (2HCl) is gamma-aminobutyric acid (GABA) agonists and its major effects appear to be on the central nervous system. Piperazine was the anthelmintic with the greatest number of reports of toxicoses and suspected toxicoses in cats. Piperazine neurotoxicity in cats and dogs usually was manifested by muscle tremors, ataxia, and/or behavioral disturbances within 24 hours after estimated daily dose(s) between 20 and 110 mg/kg[1]. For di-substituted derivatives, ciprofloxacin was selected and hybrids were synthesized via substitution at piperazinyl-N4. The reaction of piperazinyl-NH of ciprofloxacin with selected drugs resulted in pronounced growth inhibition of standard as well as resistant bacterial strains[2]. The parent piperazine 6 was found to exhibit a reasonable activity toward the HeLa and MDA MB 231 tumor cell lines (IC50= 9.2 and 8.4 μΜ, respectively)[3]. Piperazine adipate (10 mM) causes mortality of A. galli and H. gallinae after a maximum of 30 min exposure, inhibits malate oxidation by 78%, and inhibits aldolase activity in both parasites. Piperazine adipate (10 mM) also inhibits cholinesterase activity by 96% in Ascaridia galli (A. galli) and 93% in Heterakis gallinae (H. gallinae). Piperazine adipate inhibits oxaloacetate reduction by 26% and 55% in A. galli and H. gallinae, resepctively[4].

PKI-179 is a potent, orally active compound that functions as a dual PI3K/mTOR inhibitor. It demonstrates IC50 values of 8 nM for PI3K-α, 24 nM for PI3K-β, 74 nM for PI3K-γ, 77 nM for PI3K-δ, and 0.42 nM for mTOR. Additionally, it is effective against E545K and H1047R mutations, with IC50s of 14 nM and 11 nM, respectively. In vivo studies have shown that PKI-179 possesses anti-tumor capabilities[1][2].

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.

CC-90005 is a potent, selective and orally active inhibitor of protein kinase C-θ (PKC-θ), with an IC50 of 8 nM. CC-90005 shows selectivity for PKC-θ over PKC-δ (IC50=4440 nM). CC-90005 can inhibit T cell activation by IL-2 expression[1]. CC-90005 shows the exquisite selectivity of CC-90005, with IC50s for all other family members of >3 μM[1].CC-90005 is a moderate inhibitor of both CYP2C9 (IC50=8 μM) and CYP2C19 (IC50=5.9 μM) in human liver microsomes[1].CC-90005 inhibits IL-2 expression in LRS_WBC human PBMCs, with an IC50 of 0.15 μM[1].CC-90005 (1-10 μM; 24 h) inhibits T cell proliferation in PBMCs by 51% at 1 μM and 88% at 3 μM[1]. CC-90005 (3-30 mg/kg; p.o. twice daily for 4 days) significantly reduces the popliteal lymph node (PLN) size in a model of chronic T cell activation[1].CC-90005 (100 mg/kg; a single p.o.) significantly inhibits plasma and spleen IL-2 release by 51 and 54%, respectively[1].CC-90005 exhibits reasonable oral bioavailability (66 and 46%) and Cmax (1.18 and 1.2 μM) following oral administration (10 and 3 mg/kg) in rat and dog, respectively[1].CC-90005 exhibits the mean residence time (0.52 and 2.0 h), CL (69.1 and 20.5 mL/min/kg) and Vss (2.11 and 2.44 L/kg) following intravenous administration (2 and 1 mg/kg) in rat and dog, respectively[1]. [1]. Papa P, et, al. Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005. J Med Chem. 2021 Aug 26;64(16):11886-11903.

AM679 is a potent and selective FLAP inhibitor with IC50s of 2.2 nM/0.6 nM/154 nM for FLAP binding/hLA/hWB respectively. IC50 value: 2.2 nM/0.6 nM/154 nM(FLAP binding/hLA/hWB) [1] AM679 showed an improved CYP inhibition profile (IC50 3A4 = 16.7 lM, 2C9 =

LEO 39652, a dual-soft PDE4 inhibitor, demonstrates potent inhibition of PDE4 subtypes A, B, C, and D with respective IC50 values of 1.2 nM, 1.2 nM, 3.0 nM, and 3.8 nM. Additionally, it inhibits TNF-α with an IC50 of 6.0 nM, indicating its potential for topical Atopic dermatitis (AD) research [1].