Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.

Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.

Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring.

A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

Pantolactams as androgen receptor antagonists for the topical suppression of sebum production.

A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.

Rational design of a topical androgen receptor antagonist for the suppression of sebum production with properties suitable for follicular delivery.

A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.

Crew resource management improved perception of patient safety in the operating room.

To improve safety in the operating theater, a company of aviation pilots was employed to guide implementation of preprocedural briefings. A 5-point Likert scale survey that assessed the attitudes of operating room personnel toward patient safety was distributed before and 6 months following implementation of the briefings. Using Mann-Whitney analysis, the survey showed a significant (P < .05) improvement in 2 questions (of 13) involving reporting error and 2 questions (of 11) involving patient safety climate. When analyzed by occupation, there were no significant changes for faculty physicians; for resident physicians, there was a significant improvement in 1 question (of 13) regarding error reporting. For nurses, there were significant improvements in 3 questions (of 4) involving teamwork, 1 question (of 13) involving reporting error, and 3 questions (of 11) regarding patient safety climate. These results suggest that aviation-based crew resource management initiatives lead to an improved perception of patient safety, which was largely demonstrated by nursing personnel.

Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor.

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.

Lessons from Hurricane Rita: the University of Texas Medical Branch Hospital's evacuation.

In September 2005, the University of Texas Medical Branch at Galveston (UTMB) was threatened by Hurricane Rita, a category five storm. Abandoning its historic practice of clearing the hospital of all but the sickest patients, UTMB rapidly organized and conducted the first total evacuation in its 114-year history. The authors report how this was accomplished and lessons learned. Specific factors were crucial for success, including identifying an incident commander with sole authority to make decisions, developing and communicating a set of guiding principles, setting patient safety as our top priority, establishing an incident command center that consolidated vital institutional functions, avoiding delays in deciding to evacuate, identifying strategic partners, selecting essential personnel who would not be distracted by personal concerns during the emergency, and conducting periodic trial runs of emergency preparedness. Complex demands for communication were not met as well as was hoped. Technical problems were encountered with some communication devices that proved inoperable; trial runs would have probably revealed these problems in advance. Also, in-transit communication could be improved-not always knowing which patients were where, what vehicles were mired in stalled traffic, and what relocations occurred impeded optimal communication with patients' family members. Finally, a system ensuring that the recipients of UTMB's electronic records had the proper software to receive them would have facilitated communication and helped record keeping. The authors encourage physicians, as essential members of the health care team, to become better prepared to respond to disasters.

Improving perceptions of patient care--a nursing education and nursing practice initiative.

In January 2005, the University of Texas Medical Branch (UTMB) School of Nursing and the UTMB Hospitals and Clinics launched the first phase of a project to improve perceptions of patient care on the part of nursing faculty and nursing clinicians. A finding on the UTMB annual employee satisfaction survey that nursing faculty and clinicians tended to rate quality of UTMB patient care lower than other UTMB employees provided the impetus for the initiative. When UTMB colleagues noticed the findings, various entities including human resources and the Faculty Senate called for explanations from the dean of the School of Nursing, the chief nursing officer, and the CEO for the hospitals and clinics. In the process of attempting to give reasons for the findings, each of us determined we would take definitive action to address the situation. This article describes our accomplishments for Phase 1 of the initiative. Beginning with a vision for a productive professional community characterized by a pedagogical partnership between nursing education and practice, we share the processes we followed to (1) achieve mutual understanding among task force members, (2) obtain input on perceptions from nursing colleagues, (3) identify the clinical and nursing education aspects of the perceptions, (4) reach consensus on target perceptions for Phase 2 of the project, and (5) outline the next steps for the project.

A highly efficient procedure for 3-sulfenylation of indole-2-carboxylates.

A highly efficient one-pot procedure for 3-sulfenylation of 2-carboxyindoles is described. Treatment of thiols with N-chlorosuccinimide at -78 degrees C in CH(2)Cl(2) affords sulfenyl chlorides in situ that readily react with 2-carboxyindoles to give 3-thioindoles in high yields. This new method is milder, produces less waste, and is compatible with a wide range of thiol and indole functionality. [reaction: see text]

Inhibitors of lipoprotein(a) assembly.

Compounds of the general structure A and B were investigated for their activity as lipoprotein(a), [Lp(a)], assembly (coupling) inhibitors. SAR around the amino acid derivatives (structure A) gave compound 14-6 as a potent coupling inhibitor. Oral dosing of compound 14-6 to Lp(a) transgenic mice and cymologous monkeys resulted in a>30% decrease in plasma Lp(a) levels after 1-2 weeks of treatment at 100 mg/kg/day.