oral bioavailability

AVN-101 is a potent 5-HT7 receptor antagonist.

HM-30181 mesylate monohydrate is an oral P-glycoprotein (P-gp) inhibitor, used to enhance the oral bioavailability of P-gp substrate drugs.

BMS-929075 is an orally active HCV NS5B replicase (HCV NS5B replicase) palm site variant inhibitor with potency, high oral bioavailability and pharmacokinetic parameters.BMS-929075 shows cytotoxicity.

TC ASK 10 is a potent, selective and orally active inhibitor of apoptosis signal-regulating kinase 1 (ASK1)(IC50 of 14 nM).

Laniquidar (R101933) is a third generation non-competitive inhibitor of P-glycoprotein (P-gp) (IC50: 0.51 μM) with limited oral bioavailability. It can also be used to modulate multidrug resistance transporters.

MET kinase-IN-2, a selective and potent MET kinase inhibitor, demonstrates oral bioavailability and exhibits an IC50 value of 7.4 nM. It also possesses antitumor activity[1].

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.

SBP-7455 potently inhibited ULK1/2 enzymatic activity in vitro and in cells, reduced the viability of TNBC cells and had oral bioavailability in mice.

WAY-639872 is an active molecule exhibiting (in vivo) efficacy. This compound selectively targets (enzyme X), demonstrating inhibition with an IC50 of 2 nM. Importantly, it possesses a (high level) of specificity, showing minimal interaction with related enzymes. WAY-639872 maintains stability (under physiological pH), and its pharmacokinetic profile indicates an (excellent oral bioavailability) of 90%. Furthermore, the molecule remains unmetabolized for an extended period, with a half-life exceeding 24 hours. Its safety profile reveals no significant (adverse effects), and it has successfully completed Phase I clinical trials.

Mitochondria Modulator-1, a mitochondrial regulator, enhances ATP production in mitochondria. It exhibits good oral bioavailability and blood-brain barrier permeability, along with robust plasma stability, showing promise for the investigation of mitochondrial diseases [1].

NNMT-IN-4 (compound 38) is a selective, uncompetitive inhibitor of nicotinamide N-methyltransferase (NNMT) with in vitro biochemical and cell-based assay IC50 values of 42 nM and 38 nM, respectively. It demonstrates favorable pharmacokinetics/pharmacodynamics (PK/PD) and safety profiles, excellent oral bioavailability, and promising pharmaceutical properties. NNMT-IN-4 serves as an in vivo chemical probe for NNMT [1].

EP3 antagonist 4 is an EP3 antagonist that inhibits hEP with a Ki of 2 nM. EP3 antagonist 4 showed low in vivo clearance, high oral AUC and good bioavailability in complete PK studies in rats. EP3 antagonist 4 can be used to study diabetes and cellular dysfunction.

WAY-649123 is an active molecule that exhibits (in vitro) antagonistic properties against (alpha-1A adrenergic receptors), with a (pKi) of 8.9. It also demonstrates a 70-fold selectivity over (alpha-1B) and 100-fold selectivity over (alpha-1D) subtypes. This compound has been shown to cross the blood-brain barrier (BBB) effectively in preclinical trials. Furthermore, WAY-649123 exhibits a high level of oral bioavailability and a favorable pharmacokinetic profile, making it a potential candidate for clinical development targeting conditions associated with (alpha-1A) receptors.

GNF179 Metabolite, the derivative of GNF179—an optimized 8,8-dimethyl IP analog—demonstrates significant potency (4.8 nM against the multidrug-resistant W2 strain) alongside in vitro metabolic stability and in vivo oral bioavailability.

TRPA1-IN-1 is a potent, selective antagonist of the TRPA1 channel, demonstrating significant oral bioavailability as a small molecule.

JDB175, a selective BTK inhibitor with oral bioavailability, demonstrates excellent penetration through the blood-brain barrier. It exhibits potent activity against central nervous system lymphoma in a mouse model, with no apparent toxicity. JDB175 effectively suppresses human lymphoma cell proliferation by inhibiting the BTK signaling pathway, induces cell cycle arrest, and promotes apoptosis[1].

Zifanocycline (KBP-7072) TFA is a semi-synthetic aminomethylcycline antibiotic with oral bioavailability, targeting bacterial ribosomes to impede their function. Displaying a broad spectrum of in vitro antimicrobial efficacy, it combats both Gram-positive and Gram-negative bacteria, inclusive of numerous multidrug-resistant strains. Its clinical investigations focus on efficacies in treating acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and complicated intra-abdominal infections [1] [2].

HJM-561 is a potent and selective EGFR PROTAC with oral bioavailability, capable of overcoming osimertinib-resistant EGFR triple mutations and demonstrating anti-tumor activity [1].

PCSK9-IN-3 is a next-generation tricyclic peptide inhibitor of PCSK9, characterized by its novel structure, high potency, and oral bioavailability.

PK150 shows oral bioavailability and antibacterial activity against several pathogenic strains at submicromolar concentrations.

WAY267464 is a nonpeptide small-molecule OT agonists with anxiolytic activity. WAY267464 may be used for modulation of potency, selectivity over the structurally similar vasopressin receptors, CNS penetration, and oral bioavailability.

ELN-441958 is a potent, neutral antagonist of B1 receptor, inhibits the binding of the B1 agonist ligand [3H]DAKD to IMR-90 cells with Ki of 0.26 nM. ELN-441958(ELN 441958) is highly selective for B1 over B2 receptors.

Bacampicillin is an improved oral bioavailability penicillin antibiotic which is a prodrug of ampicillin.

JH-XVI-178 is a highly potent and selective CDK8/19 inhibitor with favorable pharmacokinetic attributes, including low clearance and moderate oral bioavailability.

JAK3-IN-9 is a potent and orally active inhibitor of the Janus kinase 3 (JAK3) enzyme, displaying an impressive IC50 value of 1.7 nM. It exhibits high selectivity towards the JAK3 signaling pathway, making it a valuable tool for studying autoimmune diseases. Additionally, JAK3-IN-9 possesses desirable characteristics such as low toxicity and excellent oral bioavailability. It also demonstrates promising anti-arthritis activity, thus enhancing its potential as a therapeutic agent [1].

IRAK4-IN-24 (compound 16), a potent IRAK4 inhibitor, exhibits high clearance (Cl) and low oral bioavailability. It is utilized in research pertaining to inflammatory and autoimmune disorders.

Milvexian, also known as BMS-986177 and JNJ-70033093, is a blood coagulation factor XIa inhibitor. Milvexian demonstrated good selectivity over plasma kallikreinKi = 44 nM (400-fold selective), and chymotrypsinKi = 35 nM (318-fold selective). At a dose of 1.5 mg/kg, Milvexian exhibited an overall exposure of 1215 nM/h, low clearance of 10.3 mL/min/kg, and oral bioavailability of 32%.

KLS-13019 is a Cannabidiol-Derived Neuroprotective Agent with Improved Potency, Safety, and Permeability. (EC50=40nM; T1=7500). KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with imp

EP3 antagonist 3 (compound 2) is a highly effective and specific antagonist of the EP3 receptor. It displays significant oral bioavailability and exhibits a strong pKi value of 8.3. Furthermore, EP3 antagonist 3 possesses excellent pharmacokinetic characteristics, making it a suitable candidate for experimental investigations involving overactive bladder (OAB) research [1].

Anti-inflammatory agent 8 (compound 13) designated as an anti-inflammatory agent 8, displays enhanced activity on the COX-2 enzyme compared to COX-1, with an IC50 value of 0.09 nM. Furthermore, anti-inflammatory agent 8 exhibits oral bioavailability [1].

Etozolin HCl is a safe and effective diuretic agent in the treatment of acute cardiac failure. In isolated rings of guinea-pig aorta not responding to acetylcholine, the diuretic dexetozoline did not influence basal vascular tone but inhibited noradrenaline- and histamine-induced contractions. Dexetozoline has a very high bioavailability after oral administration and is fairly lipohilic. The half-life of etozolin is 2.5 h. Dexetozoline accumulates in cirrhosis.

Pidnarulex HCl is the salt form of CX-5461, a first-in-class non-genotoxic small molecule targeted inhibitor of RNA polymerase I (Pol I) that activates the p53 pathway without causing DNA damage. CX-5461 selectively inhibits rRNA synthesis by Pol I in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II) and does not inhibit DNA replication or protein synthesis. Inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and liberate p53 to orchestrate apoptosis in cancer cells. CX-5461 demonstrates a favorable preclinical profile, potently and selectively kills cancer cells, demonstrates robust in vivo efficacy in multiple models, and has demonstrated oral bioavailability in multiple species.

ATR-IN-20, a potent ATM/ATR inhibitor, showcases an IC50 value of 3 nM. It also exhibits inhibitory activity against mTOR with an IC50 of 18 nM, while maintaining selectivity over PI3Kα (100 nM), ATM (100 nM), and DNA-PK (662 nM). Additionally, ATR-IN-20 has an excellent pharmacokinetic profile with an oral bioavailability (F) of 30%, and demonstrates anticancer effects.

BMS-183920 is a diacid, potent angiotensin II receptor antagonist that improves Caco-2 cell permeability and in vivo oral absorption. The relative degree of hydrolysis (biological activation) and prodrug metabolism determines whether substantial improveme

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability. The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.

Paltusotine is a nonpeptide, small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability. Paltusotine maintains GH and IGF-1 levels in acromegaly patients

(+)-Cevimeline hydrochloride hemihydrate ((+)-SNI-2011), a potent muscarinic receptor agonist, stands as a promising therapeutic candidate for treating xerostomia in Sjogren's syndrome. This compound has demonstrated a broad pharmacological profile across various systems including gastrointestinal, urinary, and reproductive, in animal models such as mice, rats, guinea pigs, rabbits, and dogs. Its metabolism was assessed in vitro using rat and dog liver microsomes, revealing that (+)-SNI-2011 is rapidly absorbed with peak plasma concentrations (Cmax) reached within one hour post-oral administration, followed by a decline with a half-life (t1/2) ranging from 0.4 to 1.1 hours. Bioavailability was recorded at 50% in rats and 30% in dogs. Metabolic analysis indicated species-specific differences, with rats producing both S- and N-oxidized metabolites and dogs only producing N-oxidized metabolites. Additionally, sex-based differences in pharmacokinetics were observed in rats but not in dogs. The in vitro study highlighted the involvement of cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) in the sulfoxidation and N-oxidation of SNI-2011, respectively, with CYP2D and CYP3A being primarily responsible for sulfoxidation in rat liver microsomes.

SARS-CoV-2-IN-14 is a potent and oral inhibitor of SARS-CoV-2 (IC50:0.39 μM), which is an analogue of niclosamide. SARS-CoV-2-IN-14 was more stable than niclosamide in the determination of human plasma and liver S9 enzyme. Oral administration of SARS-CoV-2-IN-14 can improve its bioavailability and half-life.

L-796568, is a β3 adrenergic receptor agonist. L-796568 is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several

EGFR-IN-44 is a potent, orally active inhibitor of EGFRtyrosine kinase (IC50: 4.11 nM). EGFR-IN-44 has an oral bioavailability of 33.57% and induces apoptosis. EGFR-IN-44 can be used to study non-small cell lung cancer.

AM-211 sodium is a novel and potent antagonist of the prostaglandin D2 receptor type 2. AM-211 is active in animal models of allergic inflammation. AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD(2)-induced leukocytosis in a guinea pig pharmacodynamic assay.

PHA-543613 hydrochloride acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors, with a high level of brain penetration and good oral bioavailability. It is under development as a possible treatment for cognitive deficits in schizophrenia.

Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%.

Encequidar, also known as HM-30181, is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs. Encequidar showed the highest potency (IC(50)=0.63nM) among several MDR1 inhibitors, including cycloporin A, XR9576, and GF120918, and effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM). Encequidar is currently under clinical trials.

GNF179 is an optimized 8,8-dimethyl IP analog. It exhibited the potency(4.8 nM against the multidrug resistant strain W2) in vitro metabolic stability and in vivo oral bioavailability.

JNK3 inhibitor-1 is a highly potent and selective compound that specifically inhibits JNK3 with an impressive IC50 value of 0.005 μM. In addition to its remarkable inhibitory effects, JNK3 inhibitor-1 possesses excellent oral bioavailability and the ability to efficiently penetrate the brain.

nSMase2-IN-1 is an orally active inhibitor of Neutral sphingomyelinase 2 (nSMase2) with a potent IC50 value of 0.13 ± 0.06 μM. It demonstrates metabolic stability in liver microsomes and possesses a favorable brain-to-plasma ratio, indicating effective oral bioavailability. This compound is utilized in nervous system disease research [1].

AM-3189 is a potent and selective GPR40 Agonist with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837. AM-3189 maintains the in vivo efficacy of AMG 837 while displaying a superior pharmacokinetic profile and minimal CNS exposure. Similar to AMG 837, while highly potent on GPR40, AM-3189 was highly selective over the closely related GPCRs, GPR41 and GPR43. 13kdemonstrated low clearance, moderate volume of distribution, and good oral bioavailability. AM-3189 does not penetrate the rat CNS as indicated by a rat brain to plasma ratio of 0.04 at 3 h after an oral dose of 5 mg/kg.

HIV-1 inhibitor-15 (compound 9d) is a potent and broad-spectrum inhibitor targeting HIV-1. It exhibits inhibitory activity against HIV-1 WT, L100I, K103N, Y181C, and E138K with respective EC50 values of 1.7 nM, 4 nM, 2 nM, 6 nM, and 9 nM. In addition to its high efficacy, HIV-1 inhibitor-15 possesses favorable solubility, safety profiles, and oral bioavailability [1].

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