- Cholinergic agents: Effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors
-
Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.
- Moos,Bergmeier,Coughenour,Davis,Hershenson,Kester,McKee,Marriott,Schwarz,Tecle,Thomas
-
-
Read Online
- Simultaneous formation of 8H-isoquino[2,1-b][2,7]naphthyridin-8-ones and 13H-pyrido[4',3':3,4]pyrrolo[2,1-b][3]benzazepin-13-ones, a novel potential alkaloidal system
-
Condensation of 3,4-dihydro-6,7-dimethoxyisoquinoline (4) with 4-methylnicotinoyl chloride (12) in refluxing pyridine gives 5,6,13,13a-tetrahydro-2,3-dimethoxy-8H-isoquino[2,1-b][2,7]naphthyridi n-8-one (11), along with some of its 13,13a-didehydro derivative 7. A similar reaction of 4 with 4-(chloromethyl)nicotinoyl chloride (14) affords, in addition to 7, the isomeric product 10,11-dihydro-7,8-dimethoxy-13H-pyrido[4',3':3,4]pyrrolo[2,1-b][3]benz azepin-13-one (3). Analogous pairs of products are obtained from 3,4-dihydro-6,7-(methylenedioxy)- and 3,4-dihydro-6,7,8-trimethoxy-isoquinolines (15 and 18, resp). The structure of 3 was established by extensive NMR data and confirmed by single-crystal X-ray studies. Structure 7 has the ring system of the Alangium alkaloids like alangimarine (1), while the isomeric ring system 3 is predicted to be present in nature on biogenetic reasoning.
- Nagarajan,Rodrigues,Nethaji,Vohler,Von Philipsborn
-
-
Read Online
- Improved synthesis of sterically encumbered heteroaromatic biaryls from aromatic β-keto esters
-
A protocol for the synthesis of hindered 4-aryl 2-aminopyrimidines from β–keto esters is described. The process employs trifluoroethanol as an essential additive to promote the guanidine condensation reaction, enabling the synthesis of 25 aryl- and heteroaryl substituted aminopyrimidines in good yields and high purities with no column chromatography. The conditions described herein are readily scalable and have been employed in the large-scale synthesis of the clinical A2a/A2bR antagonist AB928.
- Rosen, Brandon R.,Ul Sharif, Ehesan,Miles, Dillon H.,Chan, Nicholas S.,Leleti, Manmohan R.,Powers, Jay P.
-
supporting information
(2020/03/25)
-
- Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models
-
There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42 - potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.
- Bonnefous, Céline,Payne, Joseph E.,Roppe, Jeffrey,Zhuang, Hui,Chen, Xiaohong,Symons, Kent T.,Nguyen, Phan M.,Sablad, Marciano,Rozenkrants, Natasha,Zhang, Yan,Wang, Li,Severance, Daniel,Walsh, John P.,Yazdani, Nahid,Shiau, Andrew K.,Noble, Stewart A.,Rix, Peter,Rao, Tadimeti S.,Hassig, Christian A.,Smith, Nicholas D.
-
experimental part
p. 3047 - 3062
(2010/01/16)
-
- (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6- (trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist
-
A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)4-[4-cyano-3-(trifluoromethyl)phenyl]-2, 5-dimethyl-N-[6(triflouromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED50 = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
- Kinoyama, Isao,Taniguchi, Nobuaki,Toyoshima, Akira,Nozawa, Eisuke,Kamikubo, Takashi,Imamura, Masakazu,Matsuhisa, Akira,Samizu, Kiyohiro,Kawanimani, Eiji,Niimi, Tatsuya,Hamada, Noritaka,Koutoku, Hiroshi,Furutani, Takashi,Kudoh, Masafumi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-Ichi
-
p. 716 - 726
(2007/10/03)
-
- OXYTOCIN INHIBITORS
-
This invention relates to compounds of formula (I).
- -
-
Page 103-104
(2010/02/06)
-