Nuclear receptors are ligand-activated transcription factors involved in regulating many physiologic and pathologic processes. Ligand binding to nuclear receptors leads to dissociation of co-repressors, recruitment of co-activators, and subsequent activation of gene expression. Because of their associations with many human diseases, nuclear receptors are therapeutic targets for pharmaceutical development. The pregnane X receptor (PXR, NR1I2) belongs to the nuclear receptor family. The activity of PXR can be controlled by the binding of small molecule agonists or antagonists. Because of its unique ligand binding pocket, PXR binds promiscuously to structurally diverse chemicals. PXR regulates the expression of proteins such as drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4), efflux transporter P-glycoprotein, and other multidrug resistance proteins, which are involved in metabolism and elimination of potentially harmful chemicals. PXR has been detected in various tissues including kidney, colon, brain capillaries, small intestine, and predominantly in liver, and it can be activated by various ligands that bind to its ligand binding domain (LBD). PXR forms a heterodimeric complex with RXR to activate gene transcription. The recombinant pETDuet1-hPXR-LBD/mSRC-1 plasmid (Medicilon, Shanghai, China) was transformed into Escherichia coli BL21 DE3 cells for protein expression.

SM-1200, a potent bivalent Smac mimetic, induces rapid, complete, and durable tumor regression in mice. X-linked inhibitor of apoptosis protein (XIAP) and cellular IAP1/2 (cIAP1/2) regulate apoptosis and are promising cancer therapeutic targets. Smac (second mitochondria-derived activator of caspases), also known as DIABLO, antagonizes IAP proteins. Researchers designed and synthesized new compounds based on bivalent Smac mimetics, leading to the identification of SM-1200 (compound 12). SM-1200 binds to XIAP (Ki = 0.5 nM), cIAP1 (Ki = 3.7 nM), and cIAP2 (Ki = 5.4 nM), and inhibits growth of MDA-MB-231 breast cancer (IC50 = 11.0 nM) and SK-OV-3 ovarian cancer (IC50 = 28.2 nM) cell lines. With an improved pharmacokinetic profile compared to previous bivalent Smac mimetics, SM-1200 effectively induces rapid and durable tumor regression in the MDA-MB-231 xenograft model. These findings suggest SM-1200 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development. Pharmacokinetic (PK) studies of bivalent Smac mimetics were performed in male Sprague Dawley rats (body weight: 250–270 g) by Medicilon. Before the pharmacokinetic studies, animals were carotid cannulated.

Prostate cancer (PCa) is a major global health concern. The androgen receptor (AR), a key member of the nuclear hormone receptor superfamily, is vital for prostate gland development and the maintenance of male secondary sexual characteristics. ARD-2051 is a potent and orally bioavailable AR PROTAC degrader. In vitro microsomal metabolic stability studies of AR degraders were performed in Medicilon. The in vitro plasma stability of a test compound was studied in human, mouse, rat, dog and monkey plasmas in Medicilon. Plasma protein binding of a test compound was assessed by equilibrium dialysis method with dialysis membrane strips in Medicilon. The CYP inhibition of a test compound was studied in human liver microsomes in Medicilon. PK studies in mice, rats and dogs were performed in Medicilon. In mouse, ARD-2051 has an excellent overall PK profile, with a low clearance (Cl = 3.7 ml/min/kg), a moderate volume of distribution (Vss = 1.3 L/kg), a half-life of approximately 5 h with both IV and oral routes of administration, and an excellent oral exposure with a good oral bioavailability (F) of 53%. In rat, ARD-2051 has a low-moderate clearance in rats (Cl = 10.2 ml/min/kg), a moderate volume of distribution (Vss = 1.3 L/kg), a half-life of 2-2.3 h with intravenous (IV) and oral routes of administration, and achieves an excellent oral bioavailability (F) of 82%. In dog, ARD-2051 has a low-moderate clearance (Cl = 4.6 ml/min/kg), a good volume of distribution (Vss = 2.8 L/kg), a long half-life of 8.9 h with IV route of administration and 21.1 h with oral route of administration, an excellent oral exposure (Cmax = 294 ng/ml and AUC=1822 h*mg/ml at 1 mg/kg), and an oral bioavailability (F) of 46%. These data indicate that ARD-2051 has favorable pharmacokinetic properties and excellent oral bioavailability in mice, rats, and dogs.

Jellies offer a palatable alternative to traditional tablets, improving medication adherence in children and the elderly. A study comparing different formulations of common cold medicines (syrup, jellies, and tablets) revealed that while none were bioequivalent according to FDA standards, jellies and syrup exhibited similar absorption rates and extents. Tablets, however, significantly delayed and reduced drug absorption compared to the syrup. These findings suggest that jellies can be a patient-friendly formulation with comparable bioavailability to syrup. To evaluate the effect of jelly formulation on the bioavailability of cold medicines, two types of jellies were prepared for a fixed-dose combination of acetaminophen (AAP), chlorpheniramine maleate (CPM), dextromethorphan hydrobromide (DMH), and dl-methylephedrine hydrochloride (MEH). A pharmacokinetic study was performed in beagle dogs after oral administration in Medicilon Preclinical Research (Shanghai) LLC (Shanghai, China). The plasma concentration profiles of AAP, CPM, DMH, and MEH are presented in the figure below. As shown in the initial plasma concentration profile for 4 h, the jellies and syrup showed rapid absorption of AAP, while both tablets retarded the absorption of AAP exhibiting lower Cmax and delayed Tmax. The jellies had less delay in the absorption rate and better bioavailability than the tablets.

Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis (MS), a neuroinflammatory and demyelinating disease characterized by multifocal perivascular infiltrates of immune cells. Although EAE is predominantly considered a T helper 1-driven autoimmune disease, mounting evidence suggests that activated dendritic cells (DC), which are the bridge between innate and adaptive immunity, also contribute to its pathogenesis. Sirtuin 6 (SIRT6), a NAD+-dependent deacetylase involved in genome maintenance and in metabolic homeostasis, regulates DC activation, and its pharmacological inhibition could, therefore, play a role in EAE development. The PK study was performed by Medicilon.

Colorectal tumors, in particular, often show dysregulated WNT/β-catenin signalling. G007-LK may be a candidate for use in preclinical trials to determine the efficacy of this drug in preventing growth of WNT dependent tumors. Doses of the tankyrase inhibitor G007-LK shown to be sufficient to inhibit tumor growth are well tolerated by mice within the time frames investigated. Lineage tracing from LGR5+ intestinal stem cells was reduced upon G007-LK treatment, without altering the main morphological characteristics of the intestine. Moreover, mice treated with G007-LK did not experience weight loss, suggesting that the absorptive capacity of the intestine was not negatively impacted. Medicilon Preclinical Research LCC performed the pharmacokinetic studies.

Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin. This study was conducted in a small, selected population of healthy subjects with normoglycaemia. The results suggest that Cetagliptin, at doses ≥50 mg once daily (QD), exhibited minimal accumulation, inhibited plasma DPP-4 activity by >80% over a 24-hour dosing interval, and increased active glucagon-like-1 peptide (GLP-1) levels without producing hypoglycaemia. The active GLP-1 assays were performed by Medicilon Preclinical Research LLC. Generally, Cetagliptin has favourable clinical tolerability and safety.

Heart failure (HF), known as the terminal stage of various cardiovascular diseases, is characterized by poor prognosis and high mortality. JX01 a promising anti-HF drug candidate, showed good pharmacokinetic and safety profiles. JX01 exhibits better cardiomyocyte protective effects than EMPA in vitro. JX01 exhibits lower minimum effective doses than EMPA in vivo. JX01 has good pharmacokinetic properties. Pharmacokinetic studies were commissioned by Medicilon.

​Stroke is one of the most devastating diseases affecting the health and life of human beings. TBN, a novel tetramethylpyrazine derivative armed with a powerful free radical-scavenging nitrone moiety, has been reported to reduce cerebral infarction in rats through multi-functional mechanisms of action. TBN may serve as a promising new clinical candidate for the treatment of ischemic stroke. Six Cynomolgus macaque monkeys were used for pharmacokinetic study. TBN were given intravenously at doses of 30 and 90 mg/kg, 3 monkeys for each dose. TBN (purity 99.3%) used in this study was synthesized by Medicilon.

The transmembrane (TM) anchors of many signaling receptors actually play critical roles in receptor signaling, and the diversity of mechanism with which the TM regions can promote signaling is beyond the traditional views in receptor biology. Oligomer labeling (OG-label), the soluble crosslinkable protein (SCP) used is a small protein named GB1 (M.W. = 8.4 kDa). Its N-terminus is linked to a TriNTA molecule via a crosslinker to form the TriNTA-GB1 conjugate. The target TM protein to be examined has a His6-tag. The TriNTA molecule has extremely high binding affinity to His6-tag sequence (20 ± 10 nM), which can strongly attach GB1 to the individual protomers of the TMD oligomer in bicelles. TriNTA was synthesized by Medicilon.