tolerability

Apricitabine (SPD754) is a highly selective and orally active HIV-1 reverse transcriptase inhibitor (Ki=0.08 μM), the (-) enantiomer of 2′-deoxy-3′-oxy-4′-thiocytidine (dOTC) . Apricitabine inhibits DNA polymerase α, β and γ with Ki values of 300 μM, 12 μM and 112.25 μM, respectively. Apricitabine has shown good antiretroviral therapeutic efficacy in antiretroviral HIV-infected patients, with good tolerability and low selective resistance.

The quinuclidine PHA 568487 free base is an agonist of the alpha 7 nicotinic acetylcholine receptor that was designed to mitigate the bioactivation associated with the core scaffold and subsequently remove associated liabilities with in vivo tolerability.

Nur77 modulator 1 is an effective Nur77 binder (KD = 3.58 μM) that up-regulates Nur77 expression, mediates its sub-cellular localization, induces Nur77-dependent ER stress and autophagy, and leads to cell apoptosis, demonstrating anti-hepatoma activity.

Blonanserin (AD-5423) is an atypical antipsychotic approved in Japan in January, 2008. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension.

ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. ALZ-801 is an advanced and markedly improved candidate for the treatment of Alzheimer's disease. ALZ-801 is a potent and orally available small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor, a valine-conjugated prodrug of Tramiprosate with substantially improved PK properties and gastrointestinal tolerability compared with the parent compound.

Acemetacin (TVX 1322) is a carboxymethyl ester of indometacin and a potent non-steroidal anti-inflammatory drug derived from indol-3-acetic acid, with its activity primarily attributed to its active metabolite, indomethacin. In clinical trials, acemetacin shows better gastric tolerability compared to indomethacin.

PIKfyve-IN-4 (Compound 40) is an orally active and selective phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) inhibitor, with an IC50 of 0.60 nM, and demonstrates good systemic tolerability.

Inupadenant is an orally active, highly selective A2A receptor antagonist with potent anti-tumor activity [1] and is not brain-penetrant.

The prostaglandin E receptor 4 (EP4) is one of four G protein-coupled receptors that mediate the actions of prostaglandin E2 . Binding of PGE2 to the EP4 receptor causes an increase in intracellular cyclic AMP, which plays important roles in bone formation and resorption, cancer, and atherosclerosis. KMN-80 is a substituted γ-lactam (pyrrolidinone) derivative of PGE1 that acts as a selective and potent agonist of EP4 with an IC50 value of 3 nM (IC50 = 1.4 μM for EP3 and > 10 μM for all other prostanoid receptors). In functional assays it has been shown to stimulate secreted alkaline phosphatase gene reporter activity in EP4-transfected HEK293 cells with an EC50 value of 0.19 nM, demonstrating >5,000 and 50,000-fold selectivity against EP2 and TP, respectively. KMN-80 can induce the differentiation of bone marrow stem cells from both young and aged rats into osteoblasts in vitro (EC50s = 20 and 153 nM, respectively) and exhibits favorable tolerability up to at least 10 μM, whereas the EP4 agonist L-902,688 is highly cytotoxic at similar concentrations in these cells. KMN-80 has been used to repair calvarial defects in an in vivo rat craniomaxillofacial reconstruction model (rate of reduction in defect size equivalent to BMP-2 treated rats) and to promote bone formation in a rat incisor tooth socket model.

Tinengotinib is a multikinase inhibitor targeting a series of kinases involved in cancer cell proliferation, angiogenesis, and regulation of immune response, including Aurora kinase A B, Janus kinase (JAK1 2), fibroblast growth factor receptor (FGFR1 2 3), vascular endothelial growth factor receptors (VEGFRs), and other tyrosine kinases. Tinengotinib has shown good tolerability and preliminary efficacy in clinical trials in a variety of advanced solid tumors.

PF04929113 (SNX-5422) is a synthetic, novel, small molecule Hsp90 Inhibitor. As an oral formulation that demonstrates strong efficacy and tolerability, PF04929113 is positioned as a breakthrough therapy with broad applicability across a wide range of cancers.

Antitubercular agent-20 is an orally active antitubercular agent. agent-20 showed low cytotoxicity and good tolerability in BALB c mice.

AZ0108 is an orally bioavailable, potent PARP1,2,6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies. AZ0108 has been utilized as in vitro tools and in vivo probes to investigate the biological consequences of inhibiting centrosome clustering through PARP enzymes. AZ0108 is more selective in its enzyme inhibition profile and effects on cellular pathways and phenotypes. Specifically, AZ0108 inhibits PARPs 1, 2, and 6 with approximately 100-fold selectivity against PARP3 and TNKS1. Consistent with this lack of potencytowards tankyrase, AZ0108 is not active in a DLD-1 Wnt luciferase reporter assay.

Rimegepant, also known as BMS-927711 and BHV-3000, is a potent, selective, competitive, and orally active calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraines. Rimegepant has shown in vivo efficacy without vasoconstriction effect. BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

The immunoregulator spleen tyrosine kinase (SYK) is upregulated in cutaneous lupus erythematosus (CLE). This double-blind, multicentre, Phase Ib study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of the selective SYK inhibitor GSK2646264 in active CLE lesions

BAY 1214784, a potent, selective, and orally active spiroindoline derivative compound, serves as an antagonist of the human gonadotropin-releasing hormone receptor (hGnRH-R). It notably reduces plasma luteinizing hormone levels by up to 49%, demonstrating low pharmacokinetic variability and good tolerability. This compound shows promise for research into uterine fibroids.

ROCK2-IN-5, a compound integrating structural elements from the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids, exhibits a favorable multitarget profile and tolerability. It shows potential for research in Amyotrophic Lateral Sclerosis (ALS) associated with a SOD1 mutation.

Lipid M (pKa: 6.75) is a potential carrier for mRNA vaccines, offering enhanced immune responses and increased tolerability [1].

Fontolizumab (HuZAF) is a humanised IgG1 monoclonal anti-IFN-gamma (IFN-γ) antibody with good tolerability and low immunogenicity. It is administered intravenously in clinical settings and can be used for the study of Crohn's disease.

Mazdutide (IBI-362; LY-3305677), a synthetic oxyntomodulin analog, serves as a glucagon-like peptide-1 (GLP-1R) glucagon receptor (GCGR) co-agonist. Demonstrating safety and tolerability, Mazdutide is utilized in obesity and type 2 diabetes (T2D) research [1] [2].

Nab-Paclitaxel is an albumin-bound formulation of Paclitaxel nanoparticles known for its enhanced response rates and tolerability. Leveraging albumin as a delivery vehicle, this compound achieves a favorable pharmacokinetic (PK) profile [1] [2].

Mazdutide (IBI-362; LY-3305677) TFA is a dual agonist for the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR), recognized as a long-acting synthetic oxyntomodulin analog. It demonstrates a favorable safety and tolerability profile and is utilized in research related to obesity and type 2 diabetes (T2D) [1] [2].

PTC258 is a specific, orally active modulator of the splicing of the Elongator complex protein 1 gene (ELP1), enhancing its expression both in vitro and in vivo. Additionally, PTC258 has demonstrated good tolerability in a mouse model [1].

Blonanserin-d5 is a deuterated compound of Blonanserin. Blonanserin has a CAS number of 132810-10-7. Blonanserin is an atypical antipsychotic approved in Japan in January, 2008. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension.