M.W=450-500 | Heterocyclic Building Blocks-piperidine

Owens, Timothy D.’s team published research in Clinical and Translational Science in 15 | CAS: 1971920-73-6

Clinical and Translational Science published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C26H25N5O3, Application of (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

Owens, Timothy D. published the artcilePhase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168), Application of (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, the publication is Clinical and Translational Science (2022), 15(2), 442-450, database is CAplus and MEDLINE.

Bruton′s tyrosine kinase (BTK), expressed in B cells and cells of innate immunity, including microglia, is an essential signaling element downstream of the B-cell receptor and Fc-receptors. Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential to target inflammation in the periphery and central nervous system (CNS). Tolebrutinib crosses the blood-brain barrier and potently inhibits BTK in microglial cells isolated from the CNS. A first-in-human randomized, double-blind, placebo-controlled study of tolebrutinib was conducted. The trial design consisted of five single ascending dose arms with oral administration of a single dose of 5, 15, 30, 60, and 120 mg (n = 6 per arm, n = 2 placebo), five multiple ascending dose arms with oral administration of 7.5, 15, 30, 60, and 90 mg (n = 8 per arm, n = 2 placebo) over 10 days, and one arm (n = 4) in which cerebral spinal fluid (CSF) exposure was measured 2 h after a single 120 mg dose. Tolebrutinib was well-tolerated in the study and all treatment-related treatment emergent adverse events were mild. Tolebrutinib was rapidly absorbed following oral administration with a rapid half-life of ∼ 2 h. Peripheral BTK occupancy was assessed at various timepoints by an ELISA-based readout using an irreversible probe. Assessments demonstrated extensive and prolonged peripheral BTK occupancy at steady-state with once daily doses as low as 7.5 mg. Further, CSF exposure was demonstrated 2 h after administration at 120 mg.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Correale, Jorge’s team published research in Lancet Neurology in 20 | CAS: 1971920-73-6

Lancet Neurology published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C26H25N5O3, Computed Properties of 1971920-73-6.

Correale, Jorge published the artcileBruton’s tyrosine kinase inhibitors as potential therapies for multiple sclerosis, Computed Properties of 1971920-73-6, the publication is Lancet Neurology (2021), 20(9), 689-691, database is CAplus and MEDLINE.

A review. Over the past 30 years increasing numbers of mols. have been developed for treatment of multiple sclerosis. Bruton’s tyrosine kinase is a cytoplasmic tyrosine kinase expressed by B cells and myeloid cells. Both B cells and myeloid cells (particularly microglia) are important drivers of multiple sclerosis, suggesting that inhibitors of Bruton’s tyrosine kinase, such as the irreversible inhibitors evobrutinib, tolebrutininb, and orelabrutinib, and the reversible inhibitors fenebrutinib and BIIB091, might provide therapeutic benefits for patients. Bruton’s tyrosine kinase inhibitors could provide attractive therapeutic benefits for patients with multiple sclerosis, with potential advantages over monoclonal antibodies because they might be less likely to trigger antibody responses, allergic reactions,or neutralisation of their therapeutic actions. Addnl., these inhibitors, as small mols., might be able to access the CNS and inhibit microglial activation. However, whether Bruton’s tyrosine kinase inhibitors will be more efficacious than monoclonal antibodies remains to be established.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Zheng, Jiamin’s team published research in Bioorganic & Medicinal Chemistry Letters in 38 | CAS: 1971920-73-6

Bioorganic & Medicinal Chemistry Letters published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C22H38O2, Recommanded Product: (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

Zheng, Jiamin published the artcileSmall molecule approaches to treat autoimmune and inflammatory diseases (Part I): Kinase inhibitors, Recommanded Product: (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, the publication is Bioorganic & Medicinal Chemistry Letters (2021), 127862, database is CAplus and MEDLINE.

Autoimmune and inflammatory diseases place a huge burden on the healthcare system. Small mol. (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: (1) protein kinases; (2) nucleic acid-sensing pathways; and (3) soluble ligands and receptors on cell surfaces. In this first part of the series, the focus is on kinase inhibitors that emerged between 2018 and 2020, and which exhibit increased target and tissue selectivity with the aim of increasing their therapeutic index.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Ringheim, Garth E.’s team published research in Frontiers in Immunology in 12 | CAS: 1971920-73-6

Frontiers in Immunology published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C26H25N5O3, COA of Formula: C26H25N5O3.

Ringheim, Garth E. published the artcileBruton′s tyrosine kinase (BTK) inhibitors and autoimmune diseases: making sense of BTK inhibitor specificity profiles and recent clinical trial successes and failures, COA of Formula: C26H25N5O3, the publication is Frontiers in Immunology (2021), 662223, database is CAplus and MEDLINE.

Clin. development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clin. indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clin. trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclin. and clin. studies have been reported, with addnl. information for pemphigus vulgaris (PV), Sjogren′s disease (SJ), chronic spontaneous urticaria (CSU), graft vs. host disease (GVHD), and asthma included where available. While improved BTK selectivity vs. kinases outside the TEC family improved clin. toxicity profiles, less profile distinction was evident within the TEC family. Anal. of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiol. of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Muste, Cathy’s team published research in Drug Metabolism and Pharmacokinetics in 42 | CAS: 1971920-73-6

Drug Metabolism and Pharmacokinetics published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C26H25N5O3, Safety of (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

Muste, Cathy published the artcileBTK-inhibitor drug covalent binding to lysine in human serum albumin using LC-MS/MS, Safety of (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, the publication is Drug Metabolism and Pharmacokinetics (2022), 100433, database is CAplus and MEDLINE.

Irreversible Bruton’s tyrosine kinase (BTK) inhibitor drugs are designed to bind covalently to a free-thiol cysteine in the BTK protein active site. However, these reactive drugs bind to off-target proteins as well. In this study, seven BTK-inhibitor drugs containing acrylamide warheads were incubated with human serum albumin (HSA) and analyzed using an LC-MS/MS peptide mapping approach to determine the amino acid sites of drug covalent binding. Significant adduction at the free-thiol cysteine of HSA was only observed for two of the drugs. However, significant adduction was observed for at least four lysine residues. This is just a small percentage of the 59 total lysine residues in HSA. These four lysine residues are likely partially buried, accessible to the drugs, and exist at least partially in a neutral state. The levels of adduction observed in the in-vitro exptl. conditions are only indicative of a relative propensity for adduction with the individual lysine residues of HSA, and are not in-vivo predictions. Widespread off-target lysine binding could impact clearance and bioavailability for irreversible inhibitor drugs. However, the extent of the impact on clearance may be limited in comparison to conjugation with glutathione.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Owens, Timothy D.’s team published research in Journal of Medicinal Chemistry in 65 | CAS: 1971920-73-6

Journal of Medicinal Chemistry published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C26H25N5O3, Quality Control of 1971920-73-6.

Owens, Timothy D. published the artcileDiscovery of Reversible Covalent Bruton′s Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib), Quality Control of 1971920-73-6, the publication is Journal of Medicinal Chemistry (2022), 65(7), 5300-5316, database is CAplus and MEDLINE.

Bruton′s tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncol. indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clin. efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Reich, Daniel S.’s team published research in Lancet Neurology in 20 | CAS: 1971920-73-6

Reich, Daniel S. published the artcileSafety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial, Recommanded Product: (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, the publication is Lancet Neurology (2021), 20(9), 729-738, database is CAplus and MEDLINE.

Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. We did a 16-wk, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centers (academic sites, specialty clinics, and general neurol. centers) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 mo before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 wk, then matched placebo (ie, identical looking tablets) for 4 wk; cohort 2 received 4 wk of placebo followed by 12 wk of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 wk over 16 wk. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 wk of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 wk previously, and compared with the lesions accumulated during 4 wk of placebo run-in period in cohort 2. Efficacy data were analyzed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modeling anal. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99) completed the treatment regimen and 126 were included in the primary anal. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3] of 33 in the 5 mg group; three [9] of 32 in the 15 mg group; one [3] of 33 in the 30 mg group; and four [13] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.12 wk of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clin. trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.Sanofi.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Hopkins, Brian T.’s team published research in Journal of Medicinal Chemistry in 65 | CAS: 1971920-73-6

Hopkins, Brian T. published the artcileDiscovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis, Related Products of piperidines, the publication is Journal of Medicinal Chemistry (2022), 65(2), 1206-1224, database is CAplus and MEDLINE.

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091 (I), a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclin. studies demonstrated BIB091 to be a high potency mol. with good drug-like properties and a safety/tolerability profile suitable for clin. development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem