Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764).

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.

Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects.

BACKGROUND: Vitamin B12 (cobalamin) deficiency may be caused by inadequate dietary intake of B12 or by conditions that result in malabsorption of the vitamin. Crystalline vitamin B12, usually in the form of cyanocobalamin, is administered parenterally (ie, intramuscularly) or orally for treating deficiency states. Intramuscular administration is widely accepted as a treatment method. Oral B12 supplementation is also used, but it is considered to be less reliable. OBJECTIVE: This study was conducted to compare the pharmacokinetics and tolerability of 2 oral formulations of cyanocobalamin-a marketed cyanocobalamin tablet (immediate-release B12 5 mg) and cyanocobalamin formulated with a proprietary carrier, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC)-to establish the feasibility of using an absorption enhancer with B12 to improve uptake of the vitamin. This was the first clinical study conducted with the cyanocobalamin/SNAC coformulation. METHODS: An open-label, randomized, single-dose, parallel-group study was conducted in healthy male subjects. Subjects were randomly assigned to 1 of 4 treatment groups: Treatment A subjects (n = 4) received 2 tablets of 5-mg cyanocobalamin formulated with 100-mg SNAC as part of a dose range-finding arm included to determine a dose to provide a measurable concentration of vitamin B12 at all time points when tested with the available vitamin B12 assay; treatment B subjects (n = 6) received 1 tablet of 5-mg cyanocobalamin formulated with 100-mg SNAC; treatment C subjects (n = 6) received 1 commercially available 5-mg cyanocobalamin tablet; and treatment D subjects (n = 4) received commercially available 1-mg cyanocobalamin IV. Treatment A was completed 3 weeks before treatments B, C, and D were studied. Human serum B12 was analyzed by chemiluminescence assay method. Validation procedures established that samples could be diluted up to 100 times without any effects on accuracy and precision. The pharmacokinetic properties of vitamin B12 were characterized by noncompartmental analysis. Vitamin B12 absolute bioavailability estimates were calculated between the oral (A, B, and C) and IV (D) treatments using non-baseline-adjusted vitamin B12 concentrations as well as baseline-adjusted vitamin B12 concentrations, with or without body weight adjustments. Tolerability was evaluated through review or monitoring of medical history, physical examination findings, concomitant medications, vital signs, laboratory tests (hematology, serum chemistry, and urinalysis values), electrocardiography, adverse events, and serious adverse events. RESULTS: Twenty healthy male subjects, aged 20 to 45 years, participated in this study. Based on data from treatment A, a 5-mg cyanocobalamin dose was selected for use with treatments B and C. The oral cyanocobalamin formulation containing SNAC had greater mean absolute bioavailability than the commercial oral formulation (5.09% vs 2.16%, respectively), calculated on AUC(0-last) values uncorrected for baseline, weight, or body mass index. It also had a reduced T(max) compared with the commercial formulation (0.5 hours vs 6.83 hours, respectively). The K(e) was similar between treatments (0.028 1/h vs 0.025 1/h). Comparable results were achieved using corrected values. The cyanocobalamin/SNAC formulation was well tolerated, and there were no reported adverse events. CONCLUSIONS: An oral formulation of 5-mg cyanocobalamin containing 100-mg SNAC, an absorption enhancer, provided significantly improved bioavailability and a significant decrease in T(max) for B12 in a small study of normal healthy subjects compared with a commercially available 5-mg cyanocobalamin oral formulation. Both oral formulations and commercial 1-mg cyanocobalamin IV were well tolerated.

Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models.

A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.