The de novo compound discovery platform used to develop 069A uses considerations of multiple molecular properties at both the design and synthetic compound characterization stages. While the physical properties associated with bioavailability and brain penetrance are often estimated by commercially available kinase inhibitor Tofacitinib computational algorithms as part of compound design, they are only approximations to assist in design and often deviate sig nificantly from experimentally determined values. Therefore, we determined the experimental values for lipophilicity and aqueous solubility of 069A using the protocols described in Methods. The experimentally determined lipophilicity of 069A yields a log P value of 3. 18. This value is within the range of computed and experimentally determined values found for orally bioa vailable, CNS penetrant drugs.

Similarly, the experi mentally determined aqueous solubility of 069A is 9. 54g mL, which translates to a log S value of 2. 02, and is a value within the desired range. The design and experimentally determined properties of the unformulated 069A suggest its potential to be orally bioavailable, Inhibitors,Modulators,Libraries CNS penetrant, stable and non toxic based on previous findings with this scaffold. Experi mental analyses confirmed this assumption. Spe cifically, 069A has acceptable oral bioavailability properties for use with in vivo studies. The compound is readily detected in the plasma within the earliest possible time point analyzed Inhibitors,Modulators,Libraries after oral administration to mice, with bulk clearance from plasma within 60 min after oral administration.

A similar pattern of time dependent Inhibitors,Modulators,Libraries change in concentration is seen in the brain homogenates prepared after perfusion of animals to remove any compound present in adventi tiously associated blood. The peak brain concentration of 069A is seen at 5 15 min after oral administration, with bulk compound clearance by 60 min. Inhibitors,Modulators,Libraries Compound 069A did not induce any major untoward tissue injury, as assessed by histologic screening for idiopathic liver injury. Specifically, histological assessment of liver tissue showed that oral administration of 069A at 2. 5 mg kg daily for 2 weeks did not induce any histological Inhibitors,Modulators,Libraries table 5 indices of liver tis sue injury compared with mice treated with the vehicle, and no adverse clinical effects of 069A adminis tration were observed during the course of treatment. Finally, 069A also showed acceptable metabolic stability in human liver microsomes, with 70% of the compound remaining after 10 min incubation with microsomes. Although 069A is not as metabolically stable as Minozac, it is more stable than the structurally related, clinical CNS drug Minaprine.