Category: pyridazine

Rak, Gregory D. published the artcileIntermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats, COA of Formula: C18H12ClFN6O, the publication is Journal of Applied Toxicology (2020), 40(7), 931-946, database is CAplus and MEDLINE.

Small-mol. inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclin. species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clin. trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-mol. TGFβRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathol. at systemic exposures that would have been targeted clin., preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-mo studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-mo studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-mo study was that the rats in the 3-mo study were 2 wk younger at the start of dosing. Therefore, a follow-up 1-mo study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-mo study, there was no difference in the toxicity of BMS-986260 in young (8 wk) or adult (8 mo) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.

Journal of Applied Toxicology published new progress about 2001559-19-7. 2001559-19-7 belongs to pyridazine, auxiliary class TGF-beta/Smad,TGF-beta Receptor, name is 6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile, and the molecular formula is C18H12ClFN6O, COA of Formula: C18H12ClFN6O.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Heinisch, G. published the artcileSynthesis and reactions of pyridazine derivatives. II. 4-Hydroxymethylpyridazine, Category: pyridazine, the publication is Monatsh. Chem. (1973), 104(5), 1354-9, database is CAplus.

4-(Hydroxymethyl)pyridazine (I) was obtained together with Et 2,5-dihydropyridazine-4-carboxylate by LiAlH4 or NaBH4 reduction of Et 4-pyridazinecarboxylate, the ratios depending on the reaction conditions. Reduction of 4-pyridazinecarboxaldehyde or 4-acetylpyridazine with NaBH4 gave I or 4-(1-hydroxyethyl)pyridazine, resp., in quant. yield. Treatment of I with SOCl2 gave 4-(chloromethyl)pyridazine.

Monatsh. Chem. published new progress about 50901-42-3. 50901-42-3 belongs to pyridazine, auxiliary class Pyridazine,Aldehyde, name is Pyridazine-4-carbaldehyde, and the molecular formula is C5H4N2O, Category: pyridazine.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Nakagome, Takenari published the artcileSyntheses of pyridazine derivatives. II. 3-Methoxy-6-pyridazinol 1-oxide, Recommanded Product: (6-Methoxypyridazin-3-yl)methanol, the publication is Yakugaku Zasshi (1962), 244-8, database is CAplus and MEDLINE.

cf. CA 55, 21134c. 3-Chloro-6-methoxypyridazine (I) (7.3 g.) in 50 mL. AcOH treated with 24 mL. 30% H₂O₂, kept 5 h. at 70°, the solution concentrated in vacuo, the residue made alk. with Na₂CO₃ and the product extracted with CHCl₃ gave 1.4 g. 3-methoxy-6-chloropyridazine 1-oxide (II), m. 157-8° (C₆H₆). The mother liquor from washing II with 2N NaOH gave 0.4 g. 3-methoxy-6(1H)-pyridazinone (III), plates, m. 162-3° (AcOEt). A solution of 18 g. BzO₂H in 337 mL. CHCI₃ treated with 14.5 g. I, kept 3 days at room temperature and the product treated as above gave 14.3 g. II, m. 157-8°. I (3 g.), 20 mL. AcOH, and 3.4 g. AcOK in a sealed tube heated 1.5 h. at 140-50° and the AcOH removed gave 3.6 g. III, m. 162-3°. III (4 g.) and 30 mL. POCl₃ heated 30 min. at 100° the product poured into ice-H₂O and extracted with Et₂O gave 1.5 g. 3,6-dichloropyridazine (IV), m. 68-9°. Catalytic reduction of 0.5 g. II in 3 mL. 28% NH₄OH and 30 mL. MeOH with 0.05 g. 10% Pd-C absorbed 77 mL. H and gave 0.35 g. 3-methoxypyridazine 1-oxide (V), m. 79-80°. Catalytic reduction of 0.5 g. II in 3 mL. 28% NH₄OH and 30 mL. MeOH with Pd-C (from 10 mL. 1% PdCl₂ and 0.5 g. C) absorbed 160 mL. H in 15 min. and gave 0.5 g. 3-methoxypyridazine; picrate m. 111°. II (3.2 g.), 12 mL. AcOH, and 1.64 g. AcONa in a sealed tube heated 1 h. at 150-60° and the product concentrated gave 1.64 g. 1-hydroxy-3-methoxy-5(1H)-pyridazinone (VI), m. 178-9°. A solution of 29.5 g. 3,6-dimethoxypyridazine I-oxide in 400 mL. 2N HCl heated 20 min. at 80-90° and the solution concentrated gave 25.3 g. VI, m. 178-9°. VI (2.8 g.), 2.54 g. BzCl, 0.46 g. Na and 30 mL. MeOH in a sealed tube heated 2 h. at 100° the solution concentrated and the residue extracted with CHCl₃ gave 3.1 g. 1-benzoyloxy-3-methoxy-6(1H)pyridazinone (VII), m. 86.5-87°. VI (2 g.), 2.5 g. MeI, Ag₂O (from 3 g. AgNO₃), and 20 mL. MeOH in a sealed tube heated 2 h. at 100° and the solution concentrated gave 100% 1,3-dimethoxy-6(1H)-pyridazinone, m. 66-7°. A solution of 250 mL. dry C₆H₆, 20.6 g. PhCH₂OH, and 4.4 g. Na, refluxed 1 h., after disappearance of Na, with 20 g. 3-chloropyridazine, and the product distilled gave 18 g. 3-benzyloxypyridazine (VIII), b_0.15 120-5°, m. 49-50°. VIII (6 g) and 84.5 mL. CHCl₃ containing 4.46 g. BzO₂H kept 2 days at room temperature gave 100% VIII I-oxide (VIIIa), m. 118-18.5°. Catalytic reduction of 0.5 g. VIIIa in 30 mL. MeOH with 0.05 g. 10% Pd-C absorbed 64 mL. H in 5 min.and gave 3-pyridazinol 1-oxide, m. 201-2° (decomposition). Catalytic reduction of 0.5 g. VIIIa in 30 mL. MeOH with 0.2 g. 10% Pd-C absorbed 128 mL. H in 15 min. and gave 0.25 g. 3(2H)-pyridazinone-H₂O, m. 74°. IV (21 g.) and 240 mL. CHCl₃ containing 18.7 g. BzO₂H kept 2 days at room temperature and the product concentrated gave 10.4 g. IV 1-oxide, m. 110-12°. IV 1-oxide (1 g.) and 0.33 g. 22.6% MeONa-MeOH heated several min. on a water bath, the solution acidified with AcOH and the product extracted with CHCl₃ gave 0.6 g. II, m. 155-7°.

Yakugaku Zasshi published new progress about 89532-79-6. 89532-79-6 belongs to pyridazine, auxiliary class Pyridazine,Alcohol,Ether, name is (6-Methoxypyridazin-3-yl)methanol, and the molecular formula is C6H8N2O2, Recommanded Product: (6-Methoxypyridazin-3-yl)methanol.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Nakagome, Takenari published the artcileSyntheses of pyridazine derivatives. III. Structure of 3-substituted 6-methylpyridazine N-oxides., Computed Properties of 89532-79-6, the publication is Yakugaku Zasshi (1962), 249-53, database is CAplus and MEDLINE.

3-Methylpyridazine (I) (9.7 g.) in 140 ml. AcOH, 14 ml. H₂O, and 14 ml. 30% H₂O₂ heated 8 hrs. at 80°, the AcOH removed, the residue in H₂O made alk. with Na₂CO₃, and the product extracted with CHCl₃ gave 9.3 g. liquid, b_0.5 110-13°; this in 1:1 C₆H₆CHCl₃ chromatographed through Al₂O₃ and the first eluate concentrated gave 3.9 g. I 2-oxide (II) m. 85-6° and the last effluent gave 4 g. I 1-oxide (III), m. 68-9°. Catalytic reduction of 0.1 g. II in 30 ml. MeOH with 0.5 g. 5% Pd-C absorbed 22 ml. H and gave 0.2 g. I (picrate m. 148-9°). Similarly, III yielded I. 3-Methyl-6-chloropyridazine (IV) (30 g.) and 420 ml. CHCl₃ containing 30 g. BzO₂H kept 3 days at room temperature, the solution concentrated and the residue washed with Et₂O gave 29 g. 3-chloro-6-methylpyridazine 1-oxide (V), m. 160-1°. Catalytic reduction of 2 g. V in 2 ml. 28% NH₄OH and 20 ml. H₂O at room temperature absorbed 1 mole H in 50 min. and gave 1.2 g. II, m. 85-6°; picrate m. 103-4°. 3-Methoxy-O-methylpyridazine (VI) (44 g.), 350 ml. AcOH, and 50 ml. 30% H₂O₂ kept 1 week at 40-5°, the AcOH removed, the residue in H₂O made alk. with Na₂CO₃ and the product extracted with CHCl₃ gave 41 g. VI 1-oxide (Via) m. 98-9° (AcOEt). VIa (0.7 g.) in 20 ml. 5% NaOH heated 1 hr., the solution acidified with HCl, evaporated to dryness, and the product extracted with EtOH gave 0.3 g. 6-methyl-3-pyridazinol 1-oxide, m. 201-2°. VIa (9 g.) and 60 ml. Ac₂O heated 2 hrs. at 100°, the Ac₂O removed, the residue made alk. with Na₂CO₃ and the product extracted with CHCl₃ gave 9 g. 6-methoxy-3-pyridazinemethyl acetate (VII), m. 59-61°. VI (8 g.) and 60 ml. 10% HCl refluxed 30 min. and the product treated as usual gave 4 g. 6-methoxy-3-pyridazinemethanol (VIII), m. 55-6.5°. VIII (1.6 g.), 0.8 g. SeO₂ and 25 ml. dioxane stirred 4 hrs. at 70-5°, the solution concentrated, and the residue treated with NH₂CONHNH₂ gave 6-methoxy-3-pyridazinealdehyde semicarbazone, m. 248° (decomposition).

Yakugaku Zasshi published new progress about 89532-79-6. 89532-79-6 belongs to pyridazine, auxiliary class Pyridazine,Alcohol,Ether, name is (6-Methoxypyridazin-3-yl)methanol, and the molecular formula is C6H8N2O2, Computed Properties of 89532-79-6.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Sperandio, David published the artcileStructure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor, Quality Control of 1350543-95-1, the publication is Bioorganic & Medicinal Chemistry (2019), 27(3), 457-469, database is CAplus and MEDLINE.

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochem. and cell-based assays and inhibited tumor growth in two proof-of-concept preclin. animal models.

Bioorganic & Medicinal Chemistry published new progress about 1350543-95-1. 1350543-95-1 belongs to pyridazine, auxiliary class Pyridazine,Boronic acid and ester,Boronate Esters,Boronic Acids,Boronic acid and ester, name is 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine, and the molecular formula is C18H10, Quality Control of 1350543-95-1.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Patel, Leena published the artcile2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors, Recommanded Product: 3-Ethynylpyridazine, the publication is Journal of Medicinal Chemistry (2016), 59(7), 3532-3548, database is CAplus and MEDLINE.

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematol. malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism This medicinal chem. effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.

Journal of Medicinal Chemistry published new progress about 1017793-08-6. 1017793-08-6 belongs to pyridazine, auxiliary class Pyridazine,Alkynyl, name is 3-Ethynylpyridazine, and the molecular formula is C6H4N2, Recommanded Product: 3-Ethynylpyridazine.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Velaparthi, Upender published the artcileDiscovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent, SDS of cas: 2001559-19-7, the publication is ACS Medicinal Chemistry Letters (2020), 11(2), 172-178, database is CAplus and MEDLINE.

Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochem. characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclin. species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicol. studies and also provided similar efficacy as once daily dosing.

ACS Medicinal Chemistry Letters published new progress about 2001559-19-7. 2001559-19-7 belongs to pyridazine, auxiliary class TGF-beta/Smad,TGF-beta Receptor, name is 6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile, and the molecular formula is C9H21NO3, SDS of cas: 2001559-19-7.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Tosh, Dilip K. published the artcileIn Vivo Phenotypic Screening for Treating Chronic Neuropathic Pain: Modification of C2-Arylethynyl Group of Conformationally Constrained A₃ Adenosine Receptor Agonists, Product Details of C6H4N2, the publication is Journal of Medicinal Chemistry (2014), 57(23), 9901-9914, database is CAplus and MEDLINE.

(N)-Methanocarba adenosine 5′-methyluronamides containing 2-arylethynyl groups were synthesized as A₃ adenosine receptor (AR) agonists and screened in vivo (po) for reduction of neuropathic pain. A small N⁶-Me group maintained binding affinity, with human > mouse A₃AR and MW < 500 and other favorable physicochem. properties. E_max (maximal efficacy in a mouse chronic constriction injury pain model) of previously characterized A₃AR agonist, 2-(3,4-difluorophenylethynyl)-N⁶-(3-chlorobenzyl) derivative 6a, MRS5698, was surpassed. More efficacious analogs (in vivo) contained the following C2-arylethynyl groups: pyrazin-2-yl 23 (binding K_i, hA₃AR, nM 1.8), fur-2-yl 27 (0.6), thien-2-yl 32 (0.6) and its 5-chloro 33, MRS5980 (0.7) and 5-bromo 34 (0.4) equivalent, and physiol. unstable ferrocene 36, MRS5979 (2.7). 33 and 36 displayed particularly long in vivo duration (>3 h). Selected analogs were docked to an A₃AR homol. model to explore the environment of receptor-bound C2 and N⁶ groups. Various analogs bound with μM affinity at off-target biogenic amine (M₂, 5HT_2A, β₃, 5HT_2B, 5HT_2C, and α_2C) or other receptors. Thus, we have expanded the structural range of orally active A₃AR agonists for chronic pain treatment.

Journal of Medicinal Chemistry published new progress about 1017793-08-6. 1017793-08-6 belongs to pyridazine, auxiliary class Pyridazine,Alkynyl, name is 3-Ethynylpyridazine, and the molecular formula is C11H21BO2Si, Product Details of C6H4N2.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Jacobs, Jon published the artcileDiscovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease, COA of Formula: C5H4N2O, the publication is Journal of Medicinal Chemistry (2013), 56(2), 534-546, database is CAplus and MEDLINE.

A high-throughput screen of the NIH mol. libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (I), [(R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844]. Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, I is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S_1′, S₁, and S₂ enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with I was instrumental in guiding subsequent rounds of chem. optimization. I provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.

Journal of Medicinal Chemistry published new progress about 50901-42-3. 50901-42-3 belongs to pyridazine, auxiliary class Pyridazine,Aldehyde, name is Pyridazine-4-carbaldehyde, and the molecular formula is C5H4N2O, COA of Formula: C5H4N2O.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Waechter, Gerald A. published the artcileTetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17, Category: pyridazine, the publication is Journal of Medicinal Chemistry (1996), 39(4), 834-41, database is CAplus and MEDLINE.

In search of new leads for selective inhibition of estrogen and androgen biosynthesis, resp., heterocyclic substituted 2-(arylmethylene)-1-tetralones (1-4, 9-17), 2-(arylhydroxymethyl)-1-tetralones (5-8), exo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalenes (18-24), and 3-alkyl substituted 4,5-dihydronaphtho[1,2-c]pyrazoles (25-27) were synthesized and tested for inhibitory activity toward four steroidogenic enzymes, P 450 arom, P 450 17, P 450 18, and P 450 scc, as well as another P 450 enzyme, thromboxane A₂ (TXA₂) synthase. The test compounds inhibited human placental P 450 arom, showing a wide range of inhibitory potencies. (Z)-4-Imidazolyl compound 17 was the most potent inhibitor, with a relative potency (rp) of 110 [rp of aminoglutethimide (AG) = 1, rp of fadrozole = 359]. A competitive type of inhibition was shown by the (E)-4-imidazolyl compound 16 (rp = 71). On the other hand some of these compounds inhibited rat testicular P 450 17. Maximum activity was shown by the 3-pyridyl compound 20 (rp = 10, rp of ketoconazole = 1). Compound 20 was the only compound which exhibited a marked inhibition of TXA₂ synthase (IC₅₀ = 14.5 μM; IC₅₀ of dazoxiben = 1.1 μM). Regarding selectivity toward the steroidogenic enzymes, compound 16 was relatively selective toward P 450 arom, whereas compound 20 was relatively selective toward P 450 17 (P 450 arom: K_m testosterone = 42 nM, K_i 16 = 33 nM, K_i 20 = 3 μM; P 450 17: K_m progesterone = 7 μM, K_i 16 = 9 μM, K_i 20 = 80 nM). Compounds 17 and 24 were not selective since they showed strong inhibition of P 450 arom (K_i 17 = 26 nM, K_i 24 = 0.12 μM) and P 450 17 (K_i 17 = 0.7 μM, K_i 24 = 0.11 μM).

Journal of Medicinal Chemistry published new progress about 50901-42-3. 50901-42-3 belongs to pyridazine, auxiliary class Pyridazine,Aldehyde, name is Pyridazine-4-carbaldehyde, and the molecular formula is C11H12O4, Category: pyridazine.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem