Functionalized olefin metathesis has been a goal in transition metal catalysis for some time now. This goal has driven the search for milder, more selective catalysts and the move toward the more electronegative transition metals lying further to the right in the periodic table. Acylonitrile is a functional olefin which has eluded all previous attempts at productive olefin metathesis. Herein we report the first examples of this useful reaction.In 1985, Mol and co-workers systematically studied the metathesis reactions of unsaturated nitriles in the presence of WCla-SnMe4 or Re207-Al203-SnMe4 catalyst and found that acrylonitrile would not undergo either self-metathesis or crossmetathesis reactions.' Likewise, we have found that no identifiable new products are obtained when acrylonitrile is treated with either of the two well-defined catalysts Mo(CHCMezPh)(NAr)-[oCMe(CF3)21~~ (Ar = 2,6-i-Pr&H3) or Ru(CHCHCPhz)(PQ3)2-c12.3 Indeed, the sole reported example of an olefin metathesis reaction involving acylonitrile seems to be the phosphoranecatalyzed methylene exchange reaction depicted in eq 1.4 R COrEtPh,P=/ .=/"N + CO&t(1)The now well-established Chauvin mechanism5 for olefin metathesis requires that two roles be played by terminal olefins in a productive metathetical coupling reaction. Olefins must donate alkylidene ligands, placing the olefin substituent a to the transition metal center (eq 2). They must also react as nucleophiles with electrophilic (at the metal) alkylidene intermediates, placing the olefin substituent @ on the metallacycle precursor to the coupled product (eq 3). These two roles place different steric and electronic demands on the olefin substituent, and one olefin need not (and in some cases cannot) fulfill both functions. In fact, we recently showed that selective crossmetathesis can result when different olefins from a reacting pair fulfill the two functions.6 We reasoned that acrylonitrile's failure to undergo productive self-metathesis may be due to its (1) Bosma, R. H. A,; Van Den Aardweg, G. C. N.; Mol, J. C. J. Organomet. Chem. 1985, 280, 115-22. (2) (a) Murdzek, J. S.; Schrock, R. R. Organometallics 1987, 6, 1373. (b) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O'Regan, M.low nucleophilicity and that selective cross-metathesis might result if a suitable catalyst were treated with a mixture of acrylonitrile and a more nucleophilic olefin. This indeed turned out to be the case, as illustrated in Table 1.Cross-metathesis reactions were run by treating a mixture of acrylonitrile and a second olefin with Schrock's molybdenum catalyst M~(CHCM~ZP~)(NA~)[OCM~(CF~)~]Z (5 mol %).297Initial attempts to optimize reaction conditions showed that the reaction is slowed down considerably by coordinating solvents but does not proceed well in pentane or toluene. Dichloromethane seems to represent the best compromise of coordinating and solvating ability, leading to complete conversion of starting material within 2-3 h with yields as reported in Table 1. Reactions run in Et20...
Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P < 0.001, r = 0.88). In contrast, neither ambrisentan nor tadalafil, which are vasodilators approved for the treatment of PAH, reduced mast cell number or 5-HT levels, nor were they as effective in treating the vascular remodeling as were the TPH1 inhibitors. When administered in combination with ambrisentan, the TPH1 inhibitors showed an additive effect on pulmonary vascular remodeling and pressures. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH.
Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.
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