Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity.

Selective TYK2 inhibitors as potential therapeutic agents: a patent review (2019-2021).

Introduction: Tyrosine kinase 2 (TYK2) is a member of the JAK family class of kinases that is responsible for mediating the immune response to IL-12, IL-23, and IFNα. The therapeutic value of targeting this pathway in autoimmune diseases is supported by human genetics and multiple companies are developing small-molecule inhibitors as potential new treatments.

Areas Covered: This article seeks to give a comprehensive review of the applications related to selective small-molecule TYK2 inhibition since the last publication in this journal in 2019.

Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation .

Apoptosis signal-regulating kinase 1 (ASK1) is one of the key mediators of the cellular stress response that regulates inflammation and apoptosis. To probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, we further optimized the profile of our previously reported inhibitor . This effort led to the discovery of , a potent (cell IC = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Cl = 1.

Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo.

Structural analysis of the known NIK inhibitor bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by (cell IC: 571 nM). Systematic optimization of this series of analogs led to the discovery of , a potent (cell IC: 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat K: 0.32) for in vivo proof of pharmacology studies.

Discovery of CNS-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors.

Apoptosis signal-regulating kinase 1 (ASK1) is a key mediator in the apoptotic and inflammatory cellular stress response. To investigate the therapeutic value of modulating this pathway in neurological disease, we have completed medicinal chemistry studies to identify novel CNS-penetrant ASK1 inhibitors starting from peripherally restricted compounds reported in the literature. This effort led to the discovery of , a novel ASK1 inhibitor with good potency (cell IC = 138 nM), low clearance (rat Cl/Cl = 0.

Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors.

Structural analysis of a known apoptosis signal-regulating kinase 1 (ASK1) inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor (cell IC = 1.2 μM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to and a parallel synthesis approach leading to .

Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430).

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays.

Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer.

Rational design and binding mode duality of MDM2-p53 inhibitors.

Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes.

Discovery and in vivo evaluation of dual PI3Kβ/δ inhibitors.

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis.

Structure-based design of novel inhibitors of the MDM2-p53 interaction.

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.

Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2.

Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors.

The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.

An efficient and scalable one-pot double Michael addition-Dieckmann condensation for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters.

A simple, scalable, and efficient one-pot methodology for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters from benzylic nitriles or esters and methyl acrylate promoted by potassium tert-butoxide is described. The process relies on a tandem double Michael addition-Dieckmann condensation reaction, which results in the formation of three discrete carbon-carbon bonds in a single pot, including a quaternary center. The method allows for the convenient and rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycyclohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone building blocks for use in natural products synthesis and medicinal chemistry.

Synthetic studies towards furanocembrane diterpenes. A total synthesis of bis-deoxylophotoxin.

Synthetic approaches to the furanocembrane family of natural products, e.g. lophotoxins, pukalides, bipinnatins, based on: i) an intramolecular cyclisation of an alpha,beta-unsaturated acyl radical intermediate into a conjugated enone, and ii) an intramolecular Stille coupling reaction involving a 2-stannylfuran and a vinyl iodide, are described.

Radical cyclization approach to spirocyclohexadienones.

Cyclization of an aryl radical at the ipso position of a p-O-aryl-substituted acetamide or benzamide generates oxindoles or quinolones bearing spirocyclohexadienone rings. This versatile reaction is applied to formal syntheses of the vasopressin inhibitor SR121463A and aza-galanthamine.

Radical and palladium-catalyzed cyclizations to cyclobutenes: an entry to the BCD ring system of penitrem D.

A novel approach toward the synthesis of the BCD ring system of penitrem D is described. The strategy capitalizes on the fast cyclization rates of aryl radicals into cyclobutenes and allows access to a variety of fused tricyclic structures. Radical/polar crossover reactions of precursors 24-29 promoted by samarium diiodide in the presence of HMPA and acetone allow access to the fully functionalized BCD ring system of penitrem D.