This is an investigator-and-subject blind, phase 1 study to characterize the safety, tolerability, pharmacokinetics and central and peripheral pharmacodynamics of 14-day repeated ascending doses of PF-06648671 once a day in healthy adults (part 1) and repeated doses at the maximum tolerated dose (MTD) defined in part 1 in healthy elderly subjects (part 2). The study also include an optional cohort (part 3) to evaluate the drug interaction between PF-06648671 at MTD and CYP3A probe, midazolam

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study:

1. For Part 1 and Part 3 specific: Healthy female subjects of non childbearing potential and male subjects who, at the time of screening, are between the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests).

2. For Part 2 specific: Female subjects of non childbearing potential and male subjects who, at the time of screening, are between the age of 65 and 85 years, inclusive. Subjects must be in good health as determined by the Investigator based on a detailed medical history, full physical examination (including blood pressure and pulse rate measurement), 12 lead ECG and clinical laboratory tests. Subjects with mild, chronic, stable disease eg, controlled hypertension, non insulin dependent diabetes, osteoarthritis may be enrolled if deemed medically prudent by the investigator. Subjects taking daily prescription or non prescription medications for management of acceptable chronic medical conditions must be on a stable dose of these, as defined by non change in dose for the 3 months prior to the first dose of study medication and no planned changes during the conduct of the study.

3. Female subjects of non childbearing potential must meet at least one of the following criteria:

   • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the post menopausal state;
   • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
   • Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations will be considered to be of childbearing potential.

4. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).

5. For Part 2 specific: the creatinine clearance greater than 60 mL/min using the Cockcroft Gault method.

6. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.

7. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

1. For Part 1 and Part 3 specific: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) at the discretion of the investigator.

2. For Part 2 specific: Recent (eg, last 6 months) evidence or history of unstable disease or moderate to severe conditions which would, in the Investigator's opinion, interfere with the study evaluations or impact on the safety of participating subjects including but not limited to anemia, liver disease, stroke.

3. Any condition possibly affecting drug absorption (eg, gastrectomy).

4. A positive urine drug screen.

5. History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.

6. Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of study medication, whichever is longer.

7. Screening supine blood pressure ≥140 mm Hg (systolic) or ≥ 90 mm Hg (diastolic), following at least 5 minutes of supine rest. If blood pressure (BP) is ≥ 140 mm Hg (systolic) or 90 mm Hg (diastolic), the BP should be repeated two more times, following 2 minutes rest and the average of the three BP values should be used to determine the subject's eligibility.

8. Screening supine12 lead ECG demonstrating QTcf >450 or a QRS interval >120 msec. If QTcf exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTc or QRS values should be used to determine the subject's eligibility.

9. Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary:

   • Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transminase (SGPT) 1.5x upper limit of normal (ULN);
   • Total bilirubin 1.5 x ULN; subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is ULN.

10. Male subjects with partners currently pregnant; male subjects able to father children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product or longer based upon the compound's half life characteristics.

11. For Part 1 and Part 3 specific: Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of study medication. As an exception, acetaminophen/paracetamol may be used at doses of ≤ 1 g/day. Limited use of non prescription medications that are not believed to affect subject safety or the overall results of the study may be permitted on a case by case basis following approval by the sponsor.

12. For Part 2 specific: Systemic therapy with any of the following cytochrome P450 (CYP) 3A4 strong and moderate inhibitors/inducers within 7 days or 5 half lives (whichever was longer) prior to the first dose of study medication, or during the study: phenobarbital, carbamazepine, phenytoin, rifampin, rifabutin, St. John's Wort, bosentan, modafinil, nafcillin, aprepitant, ciprofloxacin, boceprevir, clarithromycin, conivaptan, grapefruit juice, itraconazole, ketoconazole, mibefradil, nefazodone, posaconazole, telaprevir, telithromycin, voriconazole, aprepitant, diltiazem, erythromycin, fluconazole, verapamil and human immunodeficiency virus (HIV) protease inhibitors (eg, indinavir, ritonavir, nelfinavir, atazanavir, amprenavir, fosamprenavir, etc).

13. For Part 2 specific: sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index within 7 days or 5 half lives (whichever was longer) prior to the first dose of study medication, or during the study. However, this exclusion may be removed if the Part 1 results suggest low risk.

14. Herbal supplements and hormone replacement therapy must be discontinued 28 days prior to the first dose of study medication.

15. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 56 days prior to dosing.

16. History of sensitivity to heparin or heparin induced thrombocytopenia.

17. Unwilling or unable to comply with the Lifestyle Guidelines described in this protocol.

18. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.

19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

20. For Cohorts 3 5 in Part 1 specific: Subjects with a history of significant active bleeding, coagulation disorder or clinically significant finding on PT/PTT/INR at Screening.

21. For Cohorts 3 5 in Part 1 specific: Subjects with lower spinal malformations (on physical examination or lumber X ray), local spinal/skin infection, or other abnormalities that would exclude puncture (LP).

22. For Cohorts 3 5 in Part 1 specific: Subjects with allergy to lidocaine or its derivative.

23. Use of tobacco or nicotine containing products in excess of the equivalent of 5 cigarettes per day.

24. Subjects who answer "Yes" to the Columbia Suicide Severity Rating Scale (C SSRS) questions 4 or 5. In addition, subjects deemed by the investigator to be at significant risk of suicidal or violent behavior should be excluded.

25. Subjects who have attempted suicide in the past.

26. Subjects who have unexplained history of sudden death in their family.