138647-49-1Relevant articles and documents
Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: Novel, potent, selective, and orally bioavailable inhibitors of βII tryptase
Levell, Julian,Astles, Peter,Eastwood, Paul,Cairns, Jennifer,Houille, Olivier,Aldous, Suzanne,Merriman, Gregory,Whiteley, Brian,Pribish, James,Czekaj, Mark,Liang, Guyan,Maignan, Sebastien,Guilloteau, Jean-Pierre,Dupuy, Alain,Davidson, Jane,Harrison, Trevor,Morley, Andrew,Watson, Simon,Fenton, Garry,McCarthy, Clive,Romano, Joseph,Mathew, Rose,Engers, Darren,Gardyan, Michael,Sides, Keith,Kwong, Jennifer,Tsay, Joseph,Rebello, Sam,Shen, Liduo,Wang, Jie,Luo, Yongyi,Giardino, Odessa,Lim, Heng-Keang,Smith, Keith,Pauls, Henry
, p. 2859 - 2872 (2005)
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase β is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified β-amidoester benzamidines as potent inhibitors of recombinant human βII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
Synthesis of 2-or/and 6-methylated analogues of isoguvacine (1,2,3,6-tetrahydropyridine-4-carboxylic acid) a GABAA agonist
Rohr, Markus,Chayer, Sa?d,Garrido, Fabrice,Mann, André,Taddei, Maurizio,Wermuth, Camille-Georges
, p. 2131 - 2138 (1996)
1,2,3,6-Tetrahydropyridine-4-carboxylic acid (isoguvacine) and related 2-and/or 6-methylated analogues (1-4) were synthesized using the methoxycarbonylation [Pd(OAc)2, PPh3, CO, MeOH)] of their corresponding vinylic triflates. Analogue (5), the 6-methyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid was obtained after a reductive deoxygenation of the corresponding β-keto ester.
PYRAZOLO[1,5-a]PYRIMIDIN-7(4H)-ONE INHIBITORS OF DYNEIN
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Paragraph 0043; 00142-00144, (2021/07/17)
Pyrazolo[1,5-a]pyrimidin-7(4H)-ones of formula (I) inhibit intraflagellar transport and are useful as anticancer agents and as probes of the function of dynein-dependent systems.
Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis
Cioffi, Christopher L.,Racz, Boglarka,Varadi, Andras,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Blaner, William S.,Petrukhin, Konstantin
, p. 5470 - 5500 (2019/06/07)
Retinol-binding protein 4 (RBP4) serves as a transporter for all-trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4-/- knockout mice with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retinal pigment epithelium. We describe herein the discovery of novel RBP4 antagonists 48 and 59, which reduce serum RBP4 levels by >80% in mice upon acute oral dosing. Furthermore, 59 demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that RBP4 antagonists may also have therapeutic utility for the treatment of NAFLD.