Michael Soth

Selective p38α Inhibitors Clinically Evaluated for the Treatment of Chronic Inflammatory Disorders

p38R is a member of the well characterized mitogen activatedprotein (MAP) kinase familyof serine/threonineprotein kinases. p38R is widely expressed in endothelial, immune, and inflammatory cells and plays a central role in the regulation of proinflammatory cytokine production including TNF-R, IL-1β, and IL-6. Selective blockade of any one of these cytokineswith biologic agents has proven efficacious for inflammatory diseases including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. The p38 subfamily of MAP kinases includes four isoforms (p38R, p38β, p38γ, and p38δ) that are encoded by separate genes. Analysis of differential tissue expression and activation of these isoforms in synovial tissue extracted fromRApatients has suggested that the p38R isoform is overactivated within inflamed tissue andmay be a preferred target for intervention in the disease. This expectation has prompted a huge investment by thepharmaceutical industry in thedevelopment of p38R inhibitors as potential oral disease modifying antirheumatic drugs (DMARDs). This Perspective will summarize key learnings from over 15 years of industrial experience with p38R as a drug target, with a focus on the rational design of highly selective small molecule inhibitors, followed by a discussion of data for examples 1-11 that have entered into or are recruiting for phase 2 clinical studies (summarized in Table 1). To date, these results have been disappointing.We conclude that p38R inhibition alone is unlikely to be a successful strategy toward treating chronic inflammatory disorders. Others have also concluded that “the era of optimism surrounding the use of p38 MAPK inhibition for the treatment of RA is over”.

Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis.

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.

Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase

The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

3-Amino-pyrazolo[3,4-d]pyrimidines as p38α kinase inhibitors: Design and development to a highly selective lead

Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.

Strategic Use of Conformational Bias and Structure Based Design to Identify Potent Jak3 Inhibitors with Improved Selectivity Against the Jak Family and the Kinome.

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.

Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.

Convenient Method for the 3‐Functionalization of Isoindazoles

Abstract The C‐3 position of isoindazoles is readily functionalized by metalation with lithium diisopropylamide followed by reaction with a variety of electrophiles.

SYNTHESIS OF HETEROARYL-FUSED PYRAZOLES AS P38 KINASE INHIBITORS

The synthesis of pyrazolo-pyridine, pyrimidine, pyrazine and pyridazine heterocycles is described. In addition, we report the utilization of 2,4-difluorophenoxide as a leaving group, to facilitate formation of the desired pyrazole adducts.

Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines.

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.