Modification of a dihydropyrrolopyrimidine phosphoinositide 3-kinase (PI3K) inhibitor to improve oral bioavailability

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…To remove the H-bond acceptor and recover the water solubility, Kawada et al [68] designed pyridine, benzylamine and benzamide derivatives (181, PI3KαIC 50 ~ 14-220 nM), by adding amine or amide (piperazine, morpholine) as a solubilizing group, replacing pyridine with a phenyl moiety and introducing an ortho-substituent in the phenyl group. Finally, compound 182 was identified with good pharmacokinetic profiles (oral bioavailability in monkey 8 times better than that of compound 180) and PI3Ka inhibition (PI3Kα IC 50 = 42 nM).…”

Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development

“…The methanesulfonate salt (1d) demonstrated a 4-fold increase in the kinetic solubility. However, the thermodynamic solubility decreased 2-fold for the Methylation of the quinoline core.-Methylation reduces planarity in biaryl motifs, 31 and we hypothesized that such a conformational change would increase solubility. Synthesis of compounds followed an analogous route to a previously reported procedure, 20 the details for which are presented in the Scheme S1, Supplementary Information.…”

Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective

“…These analogs had good microsomal stability across species and exhibited The chemistry focused on introducing a solubilizing group in the solvent exposed region to give compound 87. 73 Additionally, 87 incorporates an ortho-substituent which disrupts the molecular planarity and improves water solubility. The pharmacokinetic profile of 87 in mouse showed a good clearance (CL = 11.1 mL/min/kg) and oral bioavailability (F = 86%), without significant loss of inhibitory activity (PI3K⍺ = 42 nM).…”

“…After the development of 86 , Kawada et al made changes to further improve the PK profile. The chemistry focused on introducing a solubilizing group in the solvent exposed region to give compound 87 . Additionally, 87 incorporates an ortho- substituent which disrupts the molecular planarity and improves water solubility.…”