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The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is a potential molecular target for the discovery of novel bone antiresorptive agents useful for the treatment of osteoporosis. In order to design novel compounds able to selectively inhibit the osteoclast V-ATPase we firstly identified the minimal structural requirements of bafilomycin A1, a macrolide antibiotic which potently inhibits all V-ATPases. This information allowed the design of 2-(indole)pentadienamide derivatives whose optimization led to a novel class of potent inhibitors that demonstrated a high degree of selectivity for the osteoclast V-ATPase. The most interesting derivative, SB-242784, was able to inhibit bone resorption by human osteoclasts in vitro and to completely prevent ovariectomy-induced bone loss in rats when administered orally at 10 mg kg(-1) day(-1). Structure activity relationships of this class of compounds were investigated further by replacing the 2,4-pentadienoyl chain with suitable spacers able to maintain the correct orientation and distance between the indole ring and the amide moiety.

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A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K(i) = 0.8 nM; hNK-2R binding affinity, K(i) = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K(i) = 193 nM; hNK-2R binding affinity, K(i) = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed a significant binding affinity for the human mu-opioid receptor (hMOR), docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significant micro-opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.

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The objective of this investigation was to determine if there is a difference in dental age of maturation between adolescents treated in the 1970s and those treated in the 1990s. Records of 150 Caucasian patients, 8.5 to 14.5 years old and treated in a private orthodontic office between 1972 and 1974, were randomly selected; records of another 150 patients of the same race and age range but treated between 1992 and 1994 were also collected. The percentage of calcification of the mandibular canines was rated according to methods used by Demirjian, who divided tooth development into eight segments, A to H. Using stage G to compare the 1970 and 1990 patient samples, we demonstrated dental age reductions of 1.21 years for males and 1.52 years for females, and a combined reduction of 1.40 years.

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The vacuolar H+-ATPase (V-ATPase), located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A1. Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.

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Optimisation of a novel series of osteoclast ATPase inhibitors led to (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6- pentamethylpiperidin-4-yl)-2,4-pentadienamide (1) that was the most potent compound in an in vitro osteoclast ATPase assay and in human bone resorption assays. Two of the possible geometric isomers have also been prepared and shown to be significantly less potent than 1.

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Class III antiarrhythmic agents have been shown to prevent reentrant arrhythmias but also to be responsible for initiating arrhythmias characterised by afterdepolarizations and triggered activities. By combining potassium and calcium channel antagonistic actions, as with BRL-32872 (1), it might be possible to reduce the incidence of proarrhythmias albeit retaining antiarrhythmic efficacy. In the present study we synthesised and tested for their electrophysiological activity in guinea pig papillary muscle a wide panel of analogues of BRL-32872. Some qualitative relationships between compound structure and the inhibitory effect on the rapidly activating component of the delayed rectifier potassium current and/or the L-type calcium current will be presented. New derivatives depicting bell-shaped dose-response curves on action potential duration may therefore represent novel agents for improved antiarrhythmic therapy.

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In pyridazinone or thiadiazinone cardiotonic agents with one chiral centre, the PDE inhibitory action resides mainly in one enantiomer and the myofibrillar calcium sensitization mainly in the other. This phenomenon is observed when the chiral centre is located on the pyridazinone or thiadiazinone heterocycle, but cannot be extended to structures where the chiral centre is elsewhere on the molecule. For the first time a stereoselective synthesis of a 5-substituted 3,6-dihydro-6-methyl-2H-1,3,4-thiadiazine-2-one has been achieved and an absolute configuration is proposed.

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As part of a search for new cardiotonic agents significantly sensitising the myocardial contractile proteins to calcium, together with cardiac cyclic AMP-PDE inhibitory activity, we have discovered that novel 5-substituted 3,6-dihydrothiadiazin-2-ones may fulfill both properties. The sensitising effect of the contractile proteins to calcium, assessed by the shift in the calcium sensitivity of canine cardiac myofibrillar magnesium-dependent ATPase, is determined by steric and electronic requirements. The requirements for phosphodiesterase inhibition, especially that of a near-planar arrangement for the phenyl and thiadiazin-2-one ring are consistent with those already described for analogous pyridazinones. The synthesis and structure-activity relationships are discussed.

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A radiographic study of 39 cases of "closed-lock" syndrome using three radiographic projections, finding approximately equal involvement of medial and lateral poles in long-standing cases.

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