Crenolanib is an orally active, highly selective, small molecule, next generation inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase. Crenolanib, manufactured by Arog Pharmaceuticals in Dallas, is taken orally with chemotherapy. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptors (PDGFR) (isoforms PDGFRα and PDGFRβ) and Fms-related tyrosine kinase 3 (FLT3). Besides PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) (e.g. VEGFR and FGFR) or any other serine/threonine kinase (e.g., Abl, Raf) at clinically achievable concentrations. Preclinical trials have shown Crenolanib to be active in inhibiting both wild-type and mutant FLT3. Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with IC50s of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild-type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with IC50s of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo. Crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided.1Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are being planned.

Orantinib (SU-6668) is an orally bioavailable receptor tyrosine kinase inhibitor. Orantinib binds to and inhibits the autophosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), thereby inhibiting angiogenesis and cell proliferation. Orantinib also inhibits the phosphorylation of the stem cell factor receptor tyrosine kinase c-kit, often expressed in acute myelogenous leukemia cells. Orantinib was in phase II clinical trials for the treatment of breast cancer. It was also in phase III clinical trials for the treatment of hepatocellular carcinoma. However, this research was terminated in 2014. The compound was originally developed by Sugen (subsidiary of Pfizer). In 1998, a co-development agreement took place between Sugen and Taiho for the compound.

SU-14813 is an oral, multitargeted tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), KIT, and fms-like tyrosine kinase 3 (FLT-3). SU-14813 was developed as a next-generation TKI agent following sunitinib (SU-11248) designed to demonstrate optimized pharmacokinetic (PK) and tolerability profiles. SU14813 demonstrated broad and potent antitumor activity equivalent to that of sunitinib, which resulted in tumor regression, growth arrest, growth delay, and prolonged survival in established xenograft cancer models in mice. A phase II trial of SU-14813 in patients with breast cancer was completed. However, according to the Pfizer pipeline development has been discontinued.

PF-05241328 is a novel, potent and selective inhibitor of human Nav1.7 voltage-dependent sodium channels (Nav1.7). It was developed for the pain treatment. It is highly plasma protein bound. PF-05241328 was ruled out based on half-life as the peak to trough ratios for this compound on twice-daily administration would require high therapeutic indices.

PF-06273340 is a brain penetrant, orally available and potent tropomyosin-related kinase (Trk) inhibitor. PF-06273340 has a low metabolic turnover in Human liver microsomes and hepatocytes is a good substrate for efflux transporters P-glycoprotein and Breast cancer resistance protein (BCRP) and have moderate passive permeability. PF-06273340 was investigated in Phase I clinical trials for the treatment acute and chronic pain. However clinical development has been discontinued.

PF-06282999 is selective myeloperoxidase inactivator. PF-06282999 selectively activated human pregnane X receptor (PXR). Treatment of human HepaRG cells with PF-06282999 led to ∼14-fold induction in CYP3A4 mRNA and 5-fold increase in midazolam-1'-hydroxylase activity. [18F]-Fluoro-deoxy-glucose (FDG) was administered to Ldlr-/- mice with established atherosclerosis that had been treated with clinically relevant doses of PF-06282999, and reduced FDG signal was observed in animals treated with a dose of PF-06282999 that corresponded with reduced necrotic core area. PF-06282999 was developed for the treatment of acute coronary syndromes.

PF-03654746 is a potent, selective antagonist of the human H3 receptor, developed by Pfizer. It was in the clinical trial phase II for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy, Tourette syndrome as well as potential anti-allergy applications and in phase I of clinical trial for the treatment of Schizophrenia and Alzheimer's disease, but these investigations were discontinued.

PF-04634817 is a small molecule chemokine CCR2 and CCR5 receptor dual antagonist. Treatment with PF-04634817 was associated with a modest improvement in best-corrected visual acuity, which was inferior to intravitreal ranibizumab. Analysis of the primary endpoint, Urine Albumin-to-Creatinine Ratio, indicated a modest effect of PF-04634817 in reducing albuminuria in subjects with type 2 diabetes who received angiotensin receptor blocker therapy after 12 weeks of treatment. Despite the tolerable safety profile shown by PF-04634817, clinical development was discontinued in light of the modest efficacy observed.

Tofimilast is a potent phosphodiesterase-4 (PDE4) inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/ml. Tofimilast exhibited an apparent slower absorption through the rat lung after administration as a dry powder, although absorption half-life values were <1 h and therefore the significance of a formulation effect for this compound is questionable. Tofimilast was tested as a therapeutic agent against asthma and chronic obstructive pulmonary disease but development has been discontinued due to lack of efficacy.

Pfizer was developing NPBN (PF 217830), an orally administered dopamine D2 and serotonin 5-HT1A partial agonist and 5-HT2A antagonist, for the treatment of schizophrenia. PF-217830 was discontinued from development due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy.