Discovery and Lead Optimization of Atropisomer D1 Agonists with Reduced Desensitization.

The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part of 40 years. All known D1-selective agonists are catecholamines that bring about receptor desensitization and undergo rapid metabolism, thus limiting their utility as a therapeutic for chronic illness such as schizophrenia and Parkinson's disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration. An important structural feature of this series is the locked biaryl ring system resulting in atropisomerism. Disclosed herein is a summary of our hit-to-lead efforts on this series of D1 activators culminating in the discovery of atropisomer 31 (PF-06256142), a potent and selective orthosteric agonist of the D1 receptor that has reduced receptor desensitization relative to dopamine and other catechol-containing agonists.

Homicide as a medical outcome: racial disparity in deaths from assault in US Level I and II trauma centers.

BACKGROUND: Since 1900, thousands of medical journal articles have been published on the topic of racial disparities in health and medical outcomes in the United States, including overlapping disparities based on health insurance status. But research on the question of such disparities in the medical treatment of injury from assault-matters of public safety, considerable public expense, and policy debate-is lacking. METHODS: To determine differences by race and insurance status on death from intentional injury by others on and after trauma center arrival, propensity score matching is used to estimate adjusted mortality risk ratios by race and medical insurance controlling for facility, case, and injury characteristics. Analysis is based on a nationally representative sample of 100 Level I and II US trauma centers (National Trauma Data Bank 2005-2008) and includes 137,618 black and white assault cases aged 15 years and older: 35% white, and 65% black, with 46% of the whites and 60% of the blacks coded as uninsured. RESULTS: Black patients showed higher overall raw mortality rates from assault than whites (8.9% vs. 5.1%), but after propensity score matching, the black to white adjusted risk ratio for death from assault (homicide) dropped significantly across firearm, cutting/piercing, and blunt injuries. After adjustment, estimated black deaths were 29% in excess of white deaths for firearm injuries, 36% in excess for cutting/piercing injuries, and 61% in excess for blunt injuries. Uninsured blacks comprised 76% of all excess trauma center deaths from assault. CONCLUSIONS: Along with insurance status, and after excluding on-scene deaths, among patients brought to the Level I and II trauma centers, race is a substantial independent predictor of who dies from assault. Blacks, especially the uninsured, have significantly worse outcomes overall, but there is some evidence that this pattern is minimized at higher levels of injury severity. LEVEL OF EVIDENCE: I, prognostic study.

Radiolabeled divalent peptidomimetic vitronectin receptor antagonists as potential tumor radiotherapeutic and imaging agents.

The integrin receptor alphavbeta3 is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. A radiolabeled alphavbeta3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138) was previously shown to exhibit high affinity for integrin alphavbeta3 and high selectivity versus other integrin receptors. 111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and produced excellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and their evaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of the spacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteic acid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays, and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model. All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111In derivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalent agents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratios were improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver, with the agents having intermediate-length spacers (29-43 A) showing the largest improvement. As an example, 111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney, 7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeutic index for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalent effect are discussed.