25947-11-9Relevant articles and documents
Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases
Allart, Brigitte,Auberval, Marielle,Blanc, Javier,Borgonovi, Monica,Brys, Reginald,Bucher, Denis,Christophe, Thierry,Coornaert, Beatrice,De Wachter, Maxim,Duys, Inge,El Bkassiny, Sandy,Heckmann, Bertrand,Houvenaghel, Nicolas,Jagerschmidt, Catherine,Jans, Mia,Jansen, Koen,Jaunet, Alex,Lecru, Lola,Letfus, Vatroslav,Mammoliti, Oscar,Marsais, Florence,Menet, Christel,Oste, Line,Palisse, Adeline,Poljak, Tanja,Pujuguet, Philippe,Rupcic, Renata,Saniere, Laurent,Smehil, Mario,Sonck, Kathleen,Triballeau, Nicolas,Tricarico, Giovanni,Waeckel, Ludovic,Wakselman, Emanuelle
, p. 14557 - 14586 (2021/10/20)
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.
Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode
Whitehouse, Andrew J.,Libardo, M. Daben J.,Kasbekar, Monica,Brear, Paul D.,Fischer, Gerhard,Thomas, Craig J.,Barry, Clifton E.,Boshoff, Helena I. M.,Coyne, Anthony G.,Abell, Chris
, p. 10586 - 10604 (2019/10/16)
With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.
NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF FIBROSIS
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Paragraph 0249, (2019/01/21)
The present invention discloses compounds according to Formula (I) Wherein R1, R2, L, A1, A2, A3, Cy and the subscript n are as defined herein. The present invention relates to antagonists compounds of sphingosine 1-phosphate (SIP) receptor, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
Discovery of thiazolyl-phthalazinone acetamides as potent glucose uptake activators via high-throughput screening
Agrawal, Madhavi,Kharkar, Prashant,Moghe, Sonali,Mahajan, Tushar,Deka, Vaishali,Thakkar, Chandni,Nair, Amrutha,Mehta, Chirag,Bose, Julie,Kulkarni-Almeida, Asha,Bhedi, Dilip,Vishwakarma, Ram A.
supporting information, p. 5740 - 5743 (2013/10/01)
With the aim to discover orally active small molecules that stimulate glucose uptake, high throughput screening of a library of 5000 drug-like compounds was conducted in differentiated skeletal muscle cells in presence of insulin. N-Substituted phthalazinone acetamide was identified as a potential glucose uptake modulator. Several novel derivatives were synthesized to establish structure activity relationships. Identified lead thiazolyl- phthalazinone acetamide (7114863) increased glucose uptake (EC50 of 0.07 ± 0.02 μM) in differentiated skeletal muscle cells in presence of insulin. Furthermore, 7114863 was superior to rosiglitazone under similar experimental conditions without inducing PPAR-γ agonist activity thus making it a very interesting scaffold.
Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum
Johnson, Corey R.,Gorla, Suresh Kumar,Kavitha, Mandapati,Zhang, Minjia,Liu, Xiaoping,Striepen, Boris,Mead, Jan R.,Cuny, Gregory D.,Hedstrom, Lizbeth
, p. 1004 - 1007 (2013/03/13)
Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1- phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure-activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.
Synthesis, antimicrobial and cytotoxicity studies of some novel modified strobilurin derivatives
Sridhara, Ajjanna M.,Reddy, Kallam R. Venugopala,Keshavayya, Jathi,Ambika, Dasannana Malige S.,Gopinath, Vadiraj S.,Bose, Prosenjit,Goud, Sanath Kumar,Peethambar, Sanenahalli K.
scheme or table, p. 849 - 856 (2012/01/05)
A series of some new 3-isoxazoline substituted methyl-3-methoxy-2-(4-oxo-3, 4-dihydrophthalazin-1-yl)prop-2-enoate derivatives were designed and synthesized from methyl-(4-oxo-3,4-dihydrophthalazin-1-yl)acetate, which in turn was prepared from phthalic anhydride. The structures of synthesized new compounds were characterized by spectral data and studied for their antimicrobial activities and cytotoxicity. Several of these compounds showed good antimicrobial activity.
Synthesis and antimicrobial activity of 2-substituted [4-(1,3,4-oxadiazol- 2-yl methyl)] phthalazin-1(2H)-one derivatives
Sridhara, Ajjanna M.,Venugopala Reddy, Kallam R.,Keshavayya, Jathi,Kumar Goud, Palusa Sanath,Somashekar, Bankavadi C.,Bose, Prosenjit,Peethambar, Sanenahalli K.,Gaddam, Satish Kumar
scheme or table, p. 4983 - 4989 (2010/11/18)
A series of new 2-substituted [4-(1,3,4-oxadiazol-2-yl)methyl]phthalazin- 1(2H)-one derivatives 7a-h to 9a-h were designed and synthesized from methyl (4-oxo-3,4-dihydrophthalazin-1-yl)acetate (4), which in was turn prepared from phthalic anhydride. The structure of synthesized new compounds were characterized by spectral data and screened for their antimicrobial activities against various bacteria and fungi strains. Several of these compounds showed antimicrobial activity.
Process for the production of phthalazineacetic acid ester derivatives and a novel intermediate
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, (2008/06/13)
This invention relates to a process for the production of phthalazineacetic acid ester derivatives of the formula STR1 wherein R is (C1 -C4) alkyl which comprises reacting (Z)-3-oxo-1(3H)-isobenzofuranylideneacetic acid with hydrazine in the presence of a solvent; reacting the resulting mixture of the novel compound 1-hydrazino-1,2,3,4-tetrahydro-4-oxo-phthalazineacetic acid and 3,4-dihydro-4-oxo-phthalazineacetic acid with acid in the presence of a solvent; and reacting the resulting 3,4-dihydro-4-oxo-phthalazineacetic acid with acid in the presence of an alcohol. This invention also relates to the novel compound 1-hydrazino-1,2,3,4-tetrahydro-4-oxo-phthalazineacetic acid of the formula STR2 which is an intermediate formed in the process of this invention and which is useful for the production of phthalazineacetic acid ester derivatives of formula IV. The compounds of formula IV are useful for the preparation of certain heterocyclic oxophthalazinyl acetic acids and esters thereof.
