- Discovery, synthesis, and biological evaluation of thiazoloquin(az)olin(on)es as potent CD38 inhibitors
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A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasm
- Haffner, Curt D.,Becherer, J. David,Boros, Eric E.,Cadilla, Rodolfo,Carpenter, Tiffany,Cowan, David,Deaton, David N.,Guo, Yu,Harrington, Wallace,Henke, Brad R.,Jeune, Michael R.,Kaldor, Istvan,Milliken, Naphtali,Petrov, Kim G.,Preugschat, Frank,Schulte, Christie,Shearer, Barry G.,Shearer, Todd,Smalley, Terrence L.,Stewart, Eugene L.,Stuart, J. Darren,Ulrich, John C.
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p. 3548 - 3571
(2015/05/05)
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- Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists
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Hit optimization of the class of quinazoline containing histamine H 4 receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline4-amino)-N- phenylethanesulfonamide (54) (pki = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
- Smits, Rogier A.,Adami, Maristella,Istyastono, Enade P.,Zuiderveld, Obbe P.,Van Dam, Cindy M. E.,De Kanter, Frans J. J.,Jongejan, Aldo,Coruzzi, Gabriella,Leurs, Rob,De Esch, Iwan J. P.
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supporting information; experimental part
p. 2390 - 2400
(2010/09/11)
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- Substituted 4-Amino-Quinazoline Compounds with Metabotropic Glutamate Receptor Regulating Activity and Uses Thereof
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Substituted 4-amino-quinazoline compounds corresponding to formula I methods for their production, pharmaceutical compositions containing these compounds as active agents, and the uses thereof for treating or inhibiting disorders or disease states.
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Page/Page column 66
(2009/04/24)
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- Quinazolines and related heterocyclic compounds and their therapeutic use
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A compound of the formula wherein X is CR1 or N; Y is CR3 or N; R1, R3, R4, R5 and R6 are independently H, F, Cl, Br, I, or a hydrocarbon group which optionally contains one or more heteroatoms; R7 is a heterocyclic group including one or more N atoms; R' is Rx or NRyRz wherein Rx, Ry and Rz are each H or the same or different groups, including cyclic groups formed by Ry and Rz with the N atom, of up to 20 C atoms and optionally including up to 3 further heteroatoms selected from N, O and S; or a pharmaceutically acceptable salt, ester or solvate thereof, has therapeutic utility.
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Page/Page column 20
(2009/07/18)
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- Acetonitrile-mediated synthesis of 2,4-dichloroquinoline from 2-ethynylaniline and 2,4-dichloroquinazoline from anthranilonitrile
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2,4-Dichloroquinolines and 2,4-dichloroquinazolines were synthesized from 2-ethynylanilines and anthranilonitriles, respectively, using diphosgene in acetonitrile and heating at 130 °C or 150 °C for 12 hours. This reaction was applied to the synthesis of 4,6-dichloropyrazolo[3,4-d]pyrimidine (dichloro-9H-isopurine). The postulated mechanism is also described. Georg Thieme Verlag Stuttgart.
- Lee, Jae Hak,Lee, Byoung Se,Shin, Hyunik,Nam, Do Hyun,Chi, Dae Yoon
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- Novel benzopyrimidines as widened analogues of DNA bases
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(Chemical Equation Presented). We report on the synthesis, stacking, and pairing properties of a new structural class of size-expanded pyrimidine nucleosides, abbreviated dyT and dyC. Their bases are benzo-homologated variants of thymine and cytosine and
- Lee, Alex H. F.,Kool, Eric T.
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p. 132 - 140
(2007/10/03)
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- INDAZOLINONE COMPOSITIONS USEFUL AS KINASE INHIBITORS
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The present invention provides compounds of formula (I): These compounds, and pharmaceutically acceptable compositions thereof, are useful generally as kinase inhibitors, particularly as inhibitors of PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, and Aurora-2. Accordingly, compounds and compositions of the invention are useful for treating or lessening the severity of a variety of disorders, including, but not limited to, heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases.
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Page 183-184
(2008/06/13)
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- Inhibitors of Cyclic AMP Phosphodiesterase. 3. Synthesis and Biological Evaluation of Pyrido and Imidazolyl Analogues of 1,2,3,5-Tetrahydro-2-oxoimidazoquinazoline
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Hybridization of structural elements of 1,2,3,5-tetrahydro-2-oxoimidazoquinazoline ring system common to the cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitors lixazinone (RS-82856,1) and anagrelide (3) with complementary features of other PDE inhibitor cardiotonic agents prompted the design and synthesis of the title compounds 7a-d, 11, 12, and 13a,b.The necessary features of these compounds were determined within the framework of the proposed active-site models for the high affinity form of cAMP PDE inhibited by cGMP (type IV).Evaluation of these targets, both in vitro as inhibitors of platelet or cardiac type IV PDE or in vivo as inotropic agents in the pentobarbital-anesthetized dog model of congestive heart failure, showed that these structure possessed negligibly enhanced activities over the parent heterocyclic system, and remained significantly inferior to 1 in all respects.This difference is ascribed to the absence of the N-cyclohexyl-N-methylbutyramidyl-4-oxy side chain of 1.The proposal that the acidic lactam-type functionality, common to the type IV PDE inhibitor inotropic agents such as 4-6 and 8-10, mimics the polarizable cyclic phosphate moiety of cAMP suggested that the side chain of 1 may function as an effective surrogate for selected characteristics of the adenine portion of cAMP.However, the results of this study show that incorporation of adenine-like hydrogen-bonding functionalities common to other type IV PDE inhibitors into the 1,2,3,5-tetrahydro-2-oxoimidazoquinazoline system did not enhance activity to the levels observed for 1 analogues.These observations, coupled with the kinetic pattern of inhibition of type IV PDE observed for 1 and analogues, suggest that access to a secondary, lipophilic-tolerant binding site, possibly coincident with the adenine binding domain, and adjacent to the catalytic ribose-phosphate binding site of platelet and cardiac type IV PDE, is responsible for the increased potency of these compounds.
- Venuti, Michael C.,Stephenson, Robert A.,Alvarez, Robert,Bruno, John J.,Strosberg, Arthur M.
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p. 2136 - 2145
(2007/10/02)
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