John F. DeBernardis

Angiotensin ii receptor antagonists

Blockade of the renin-angiotensin system began as a way of studying the pathogenesis of cardiovascular disease with specific pharmacological probes. Oral activity, achieved by shortening the original peptide structures, transformed the probes into therapeutic agents, the angiotensin-converting enzyme (ACE) inhibitors. However, ACE is a non-specific target for blocking the renin-angiotensin enzymatic cascade. The availability of orally active drugs turned ACE inhibition into a therapeutic breakthrough but more specific blockade always seemed desirable. This goal has now been achieved with the orally active angiotensin II receptor antagonists; six are on the market and more are under development. This new class of drugs is equal in efficacy to ACE inhibitors, at least in hypertensive patients. Trials now underway will demonstrate whether angiotensin II receptor antagonists can prevent target-organ damage and reduce cardiovascular morbidity and mortality. If they do, these compounds might one day replace ACE inhibitors.Compounds are disclosed having the formula: ##STR1## The compounds of the invention are angiotensin II receptor antagonists.

MRI and CSF studies in the early diagnosis of Alzheimer's disease.

The main goal of our studies has been to use MRI, FDG‐PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimers disease (AD). A second goal has been to describe the cross‐sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI‐determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi‐automated regional boundary shift analysis (BSA‐R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1‐42 (Aβ42). Many CSF studies of MCI and AD report elevated T‐tau levels (a marker of neuronal damage) and reduced Aβ42 levels (possibly due to increased plaque sequestration). However, CSF T‐tau and Aβ42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P‐tau, tau hyperphosphorylated at threonine 231 (P‐tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P‐tau231 are accurate and specific indicators of AD‐related changes in brain and cognition. In cross‐section and longitudinally, our results show that evaluations of the P‐tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T‐tau nor P‐tauX (X refers to all hyper‐phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain‐derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI‐based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P‐tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.

Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer's disease patients

A new sandwich ELISA is described which shows specificity for tau phosphorylated at threonine 231 and preferentially reacts with Alzheimers disease (AD) brain extracts relative to other dementias. This assay was used to analyze 58 antemortem cerebrospinal fluid samples. Twenty-three of 27 AD samples (85% sensitivity) yielded signals greater than the cutoff, while only one of 31 non-AD samples (97% specificity) were greater. This indicates that detection of phosphotau in cerebrospinal fluid with this sandwich ELISA could prove useful in the diagnosis of AD.

Efficient peripheral functionalization of porphyrins

Abstract Details are given for the mild and efficient synthesis of β-substituted “capped”-porphyrins and meso -tetraphenylporphrins from the corresponding porphyrins. The nitro derivatives are cleanly reduced to β-aminoporphyrins, which are susceptible to hydrolysis but otherwise may be further derivatized on nitrogen by standard procedures. Treatment of β-nitroporphyrins with thiolate ions in DMF gave β-alkylthioporphyrins, β-arylthioporphyrins or the corresponding denitrated prophyrin, depending on the thiol.

Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment.

Cross-sectional cerebrospinal fluid (CSF) levels of tau and amyloid (A) beta (beta) are of diagnostic importance for Alzheimers disease (AD) and mild cognitive impairment (MCI). However, most longitudinal studies of tau fail to demonstrate progression. Because predominantly brain-derived proteins such as tau, have higher ventricle to lumbar ratios, we hypothesized that adjusting for the ventricular enlargement of AD would correct for the dilution of tau, and improve detection of longitudinal change. Abeta which is not exclusively brain derived, shows a ratio <1, and no benefit was expected from adjustment. In a 1 year longitudinal study of eight MCI and ten controls, we examined CSF levels of hyperphosphorylated (P) tau231, Abeta40, and Abeta42. In cross-section, MCI patients showed elevated Ptau231 and Abeta40 levels, and greater ventricular volumes. Longitudinally, only after adjusting for the ventricular volume and only for Ptau231, were increases seen in MCI. Further studies are warranted on mechanisms of tau clearance and on using imaging to interpret CSF studies.

Synthesis of “capped porphyrins”

Abstract The synthesis of “capped porphyrins” ( 10 ), ( 18 ), and ( 28 ), and their (chloro)iron(III), iron(II), cobalt (II), and zinc(II) complexes is reported. These complexes serve as models for the active site of the oxygen binding haemoproteins. In addition to reversible binding of dioxygen by each of the iron (II) porphyrin complexes, the 1-methyl-imidazole-(“C3-capped porphyrin”) iron (II) complex ( 23 ) reacts reversibly with carbon monoxide, in solution at 25°C.

Increased levels of CSF phosphorylated tau in apolipoprotein E ɛ4 carriers with mild cognitive impairment

We investigated the correlation between the apolipoprotein E 4 allele (apoE 4) carrier status, a major risk factor of Alzheimer’s disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau231P) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau231P levels were significantly higher in apoE 4 carriers compared to non-carriers (p < 0.001). Controlling for disease duration, the apoE 4 effect on P-tau231P remained significant. Our study indicates that the apoE 4 carrier status should be considered when CSF P-tau231P is evaluated as biomarker candidate of AD in MCI subjects.

Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent α-2 antagonism with moderate NE uptake inhibition

Abstract ABT-200, (±)-(1′R*, 3R*)-3-phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylenedioxy-1′-naphthalenyl)methyl]pyrrolidine, ( 1a/b ) represents the first example of a new structural class of potent α-2 antagonists which possess the additional property of norepinephrine (NE) uptake inhibition. This profile of combined activities is expected to have utility in the treatment of depression.

A new nasal decongestant, A-57219: a comparison with oxymetazoline

2‐(4‐Amino‐3,5‐dichlorobenzyl)imidazolin hydrochloride (A‐57219), has α1‐agonist/α2‐antagonist activity and was more effective and long‐acting than oxymetazoline on canine nasal mucosa, in‐vitro and in‐vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1ṁ65 μg, atomized from a 1 μg mL‐1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.

Synthesis and In Vitro evaluation of fused ring heterocyle-containing angiotensin II antagonists.

Abstract Fused ring heterocyclic analogs of A-81080 (pA2= 9.9) were synthesized and their activities in the rabbit aorta in vitro assay were measued. The best compounds (pA2 = 8.6) in series 1 had R1 = Et, R2 = H, W = X = Z = C-H, and Y = C-OMe or C-COOH. In series 2, the best compound (pA2 = 8.3) had R1 = Et, R2 = H, W = N-Me, X = C-H, and Y = N.