Heterocyclic Building Blocks-Pyridazine

Waechter, Gerald A.’s team published research in Journal of Medicinal Chemistry in 39 | CAS: 50901-42-3

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.

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).

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

Jacobs, Jon’s team published research in Journal of Medicinal Chemistry in 56 | CAS: 50901-42-3

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.

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

Tosh, Dilip K.’s team published research in Journal of Medicinal Chemistry in 57 | CAS: 1017793-08-6

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.

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.

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

Velaparthi, Upender’s team published research in ACS Medicinal Chemistry Letters in 11 | CAS: 2001559-19-7

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.

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.

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

Patel, Leena’s team published research in Journal of Medicinal Chemistry in 59 | CAS: 1017793-08-6

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.

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

Sperandio, David’s team published research in Bioorganic & Medicinal Chemistry in 27 | CAS: 1350543-95-1

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.

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.

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

Kobe, J.’s team published research in Tetrahedron in 1968 | CAS: 18087-75-7

Tetrahedron published new progress about SUBSTITUTION IMIDAZO PYRIDAZINES; IMIDAZOPYRIDAZINES; PYRIDAZINES IMIDAZO. 18087-75-7 belongs to class pyridazine, name is 3-Nitroimidazo[1,2-b]pyridazine, and the molecular formula is C6H4N4O2, Application In Synthesis of 18087-75-7.

Kobe, J. published the artcileSynthesis of pyridazine derivatives. XV. Electrophilic substitutions on imidazo[1,2-b]pyridazines, Application In Synthesis of 18087-75-7, the main research area is SUBSTITUTION IMIDAZO PYRIDAZINES; IMIDAZOPYRIDAZINES; PYRIDAZINES IMIDAZO.

Imidazo[1,2-b]pyridazine (I), which was prepared for the first time, and several of its analogs were submitted to electrophilic substitution, such as halogenation, nitration and sulfonation. N.M.R. data for several imidazo[1,2-b]pyridazines are included and from these conclusive evidence is obtained that electrophilic substitution occurs at position 3. 17 references.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Crossland, Ingolf’s team published research in Acta Chemica Scandinavica (1947-1973) in 1972 | CAS: 7145-60-0

Acta Chemica Scandinavica (1947-1973) published new progress about pyridazine Grignard adduct conformation. 7145-60-0 belongs to class pyridazine, name is 6-Chloro-N,N-dimethylpyridazin-3-amine, and the molecular formula is C6H8ClN3, Synthetic Route of 7145-60-0.

Crossland, Ingolf published the artcileDihydropyridazines. XII. Stereochemical course of protonation of pyridazine Grignard adducts, Synthetic Route of 7145-60-0, the main research area is pyridazine Grignard adduct conformation.

Three Grignard-pyridazine adducts (I,R = Me3C, R1 = MeO; R = Ph R1 = MeO; R = Me3C, R1 = Me2N) were prepared The chem. shifts and coupling constants of the 3 ring protons of I were determined and compared with the deuterated analogs. The results showed that the proton introduced during hydrolysis assumed a pseudoaxial position and thus was identical with the proton introduced by base-catalyzed exchange of II(R2 = Me3C and Ph).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Assandri, A.’s team published research in Xenobiotica in 1985-12-31 | CAS: 17259-32-4

Xenobiotica published new progress about MDL 899 metabolism; pyrrolylpyridazinamine metabolism. 17259-32-4 belongs to class pyridazine, name is 4-(6-Chloropyridazin-3-yl)morpholine, and the molecular formula is C8H10ClN3O, Quality Control of 17259-32-4.

Assandri, A. published the artcileMetabolic pathways of the antihypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. I. Studies in the rat, Quality Control of 17259-32-4, the main research area is MDL 899 metabolism; pyrrolylpyridazinamine metabolism.

The metabolic fate of a new antihypertensive, MDL 899 (I) [86703-02-8] was studied in rats after both oral and i.v. administration (1 mg/kg). The compound underwent rapid metabolism, disappearing from the central compartment with a half-life of about 0.5 h. Plasma concentration of the parent drug and its major metabolite II [100499-32-9] following i.v. and oral administration suggest a route-dependent first-pass metabolism Ten metabolites were isolated from the urine and identified by u.v., i.r., mass and 1H NMR spectroscopy. The structure of some was confirmed by 13C NMR and chem. synthesis. All biotransformations are restricted to the pyrrole ring which undergoes oxidative cleavage followed by a series of chem. rearrangements. A minor pathway leads to the formation of Me sulphinyl and Me sulfonyl pyrroles. It is suggested that, as with natural indoles, the pyrrole might be oxidized by a 2,3-dioxygenase. All metabolites tested (3 major and 2 minor) failed to showed antihypertensive activity in spontaneously hypertensive rats.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Cookson, R. F.’s team published research in Journal of the Chemical Society, Perkin Transactions 9: Physical Organic Chemistry in 1972 | CAS: 7145-60-0

Journal of the Chemical Society, Perkin Transactions 9: Physical Organic Chemistry published new progress about Hammett basicity pyridazine; pyridazone oxygen protonation Hammett; protonation pyridazine mechanism. 7145-60-0 belongs to class pyridazine, name is 6-Chloro-N,N-dimethylpyridazin-3-amine, and the molecular formula is C6H8ClN3, Application of 6-Chloro-N,N-dimethylpyridazin-3-amine.

Cookson, R. F. published the artcileBasicities of pyridazine derivatives, Application of 6-Chloro-N,N-dimethylpyridazin-3-amine, the main research area is Hammett basicity pyridazine; pyridazone oxygen protonation Hammett; protonation pyridazine mechanism.

The Hammett free-energy relation was used to correlate the differences in basicity of six 3-(dimethylamino)pyridazines, five 3-chloropyridazines, and seven 3-pyridazones with substituent constants; protonation occurred ortho to the Me2N group of the (dimethylamino)pyridazines, meta to the Cl of the chloropyridazines, and on the exocyclic O of the pyridazones.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem