AMPA receptor antagonists.

AMPA Receptor antagonists have received considerable attention in recent years. Within the class of excitatory amino acid receptor antagonists AMPA receptor antagonists have shown excellent neuroprotection in several models of cerebral ischemia and neuronal injury. However, poor physical properties have been a major limiting factor in developing these as viable drug candidates. The quinoxaline-2,3-dione template has been the backbone of various competitive AMPA receptor antagonists such as NBQX, PNQX, YM-90K and more recently ZK200775. The SAR learned from these have been valuable for developing the AMPA pharmacophore model (Fig. 2) and has been discussed in detail in this review. There have been efforts in this area to design very selective AMPA receptor antagonists by minimizing the interaction at the NMDA associated GlyN receptors. Compounds designed by BASF and Yamanouchi have been successful in these efforts and their compounds show excellent affinity for the AMPA receptors. Efforts by Warner-Lambert and Novartis also highlight significant success in developing balanced AMPA and GlyN receptor antagonists. Non-competitive AMPA receptor antagonists are also being pursued for various neurological disorders including neuroprotection and are divided in two major classes, viz. positive and negative allosteric modulators. The physical properties of negative allosteric modulators such as GYKI 52466, which belong to the 2,3-benzodiazepinyl structural class have been significantly better. However, the in vitro activity of these compounds has been in the micromolar range and the overall class has the disadvantage of not having a high throughput assay. Other classes of compounds such as phthalazines and quinazolines are being developed and have raised hopes for the second generation of compounds in this area.

Renin inhibitors containing alpha-heteroatom amino acids as P2 residues.

A series of renin inhibitors having alpha-heteroatom amino acids as P2 substitutions has been prepared. Examples where the heteroatom is oxygen, sulfur, or nitrogen are described. Many of the compounds exhibit subnanomolar potency when tested in vitro against monkey renin. When selected compounds were tested orally in conscious, salt-depleted, normotensive, Cynomolgus monkeys, low to moderate blood pressure lowering was observed. At an oral dose of 30 mg/kg, compound 53a lowered blood pressure by a maximum of 18 mmHg at 2.5 h post-dose.

Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors.

A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.

Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.

Anomalous origin of the left coronary artery.

Coronary artery anomalies are a frequent finding in the general population and often result in sudden death. Therefore, rapid diagnosis and surgical correction are essential. Although coronary arteriography ultimately is necessary to determine the exact nature of the anomaly, two-dimensional echocardiography and radionuclide tests may provide valuable information in the initial workup of patients with chest pain, as demonstrated in the case reported here. This patient, who had angina-like symptoms, was found on cardiac angiography to have an anomalous left coronary artery rising from the right coronary sinus of Valsalva. Double coronary artery bypass grafting involving the left anterior descending and circumflex marginal vessels alleviated symptoms and resulted in improved exercise tolerance. The authors discuss theories explaining the spectrum of ischemia, infarction, and sudden death and surgical alternatives that improve survival rates.

Rest-exercise radionuclide angiographic assessment of left ventricular function in chronic aortic regurgitation: significance of serial studies in medically versus surgically treated groups.

Forty consecutive asymptomatic patients with chronic aortic regurgitation who underwent three serial yearly rest and postexercise radionuclide angiograms were compared with 27 consecutive patients with chronic aortic regurgitation and aortic valve replacement who were studied preoperatively, 3 and 15 months postoperatively. Patients were divided into four subgroups based upon the resting left ventricular ejection fraction and the functional reserve on the initial study. Of the 40 medically treated patients, 19 (47.5%) and 24 (60%) demonstrated a response at least one type lower at 12 months and 24 months, respectively. Initial functional reserve, initial duration of exercise, and the change in exercise duration during the 24 months was not associated with changes in resting or postexercise left ventricular ejection fraction. A seesaw pattern was observed between the resting and the postexercise left ventricular ejection fraction as ventricular function deteriorated. We observed in the surgical groups a reversal of the seesaw interaction between the resting and postexercise ejection fraction seen in the medical patients. In the surgical groups the left ventricular end-diastolic pressure, initial functional reserve, initial duration of exercise, and change in exercise duration postoperatively were not predictors of improvement in left ventricular function at 15 months. Comparing medical and surgical serial data, we suggest yearly radionuclide angiographic determination of rest left ventricular ejection fraction in asymptomatic patients with chronic aortic regurgitation. When the rest ejection fraction is less than 50%, exercise angiography should be performed to determine functional reserve. When functional reserve is also abnormal, surgery should be recommended.