Discovery and Optimization of p38 Inhibitors via Computer-Assisted Drug Design

Goldberg, Daniel R.; Hao, Ming‐Hong; Qian, Kevin; Swinamer, Alan; Gao, Donghong A.; Xiong, Zhaoming; Sarko, Chris; Berry, Angela; Lord, John; Magolda, Ronald L.; Fadra, Tazmeen; Kroe, Rachel R.; Kukulka, Alison; Madwed, Jeffrey; Martin, Leigh R.; Pargellis, Christopher A.; Skow, Donna; Song, Jinhua J.; Tan, Zhulin; Torcellini, Carol A.; Zimmitti, Clare; Yee, Nathan K.; Moss, Neil

doi:10.1021/jm070415w

Cited by 25 publications

(20 citation statements)

References 19 publications

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Section: Boehringer Ingelheimmentioning

confidence: 99%

“…6) [57,58], improving physicochemical properties, potency, as well as selectivity. Starting from 13, the inhibitory activity of which was equipotent to that of 10, novel compounds were designed with the tert-butyl phenyl sulfonamide functionality situated in the DFG pocket [57]. Furthermore, a pyridine template instead of the morpholine ring was chosen to interact with Met109-NH, and the flexible ethoxy linker was replaced by a rigid 5,6-fused heterocyclic ring that is able to bind in the hydrophobic pocket I.…”

Section: Boehringer Ingelheimmentioning

confidence: 99%

“…There is a trend for rigidification of single features of the inhibitors carried out in compounds from Boehringer Ingelheim [57,58], Merck [75], GlaxoSmithKline [28], and Scios [81], the Bristol-Myers Squibb analogues [84] of the Scios compounds, and the dibenzepinones [86]. Rigidification of the inhibitors may prevent induced fits in offtarget kinases, and these compounds may therefore be more selective.…”

Section: Othersmentioning

confidence: 99%

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Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Karcher¹,

Laufer

2009

CTMC

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Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta. The clinical benefit of anti-cytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of pro-inflammatory cytokines such as IL-1beta and TNF-alpha [6] suggest that p38 MAP kinase is a promising target for anti-inflammatory therapy [7-14]. Since 1993 an immense number of inhibitors of p38 MAP kinase have been characterized. To date, aside from the well known pyridinylimidazoles, multiple novel scaffolds have been identified, but only a small number have advanced into clinical phase II studies [15], probably due to high toxicity and poor selectivity [16]. To gain safe drug profiles, high potency, marginal CYP450 (cytochrome P450) interaction and toxicity, as well as high levels of selectivity would be desirable. This review will summarize current knowledge on p38 MAP kinase inhibitors and will critically discuss proceedings and strategies toward achieving selectivity and potency.

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Section: Boehringer Ingelheimmentioning

confidence: 99%

Section: Boehringer Ingelheimmentioning

confidence: 99%

Section: Othersmentioning

confidence: 99%

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Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Karcher¹,

Laufer

2009

CTMC

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“…The structural motif of 1‐aminonaphthalenes exists broadly in biologically active compounds used as a protein kinase and angiogenesis inhibitors for the treatment of cancer, Mcl‐1 inhibitors, p38 inhibitors, and BRAF inhibitors (Figure ) . Accordingly, development of efficient synthetic method for functionalized 1‐aminonaphthalene derivatives is of great importance.…”

Section: Introductionmentioning

confidence: 99%

Copper(I)‐catalyzed Cyclization Reactions of Ethyl (E)‐α‐Ethynyl‐β‐Aryl‐α,β‐Unsaturated Esters with N‐Sulfonyl Azides: Synthesis of 1‐Aminonaphthalene, 3‐Aminobenzofuran, and 3‐Aminothiobenzofuran Derivatives

Son

Han

et al. 2019

Bulletin Korean Chem Soc

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A synthetic method for ethyl 4‐(alkyl or arylsulfonamido)‐2‐naphthoates from ethyl (E)‐α‐ethynyl‐β‐aryl‐α,β‐unsaturated esters (1) and N‐sulfonyl azides (2) in the presence of 2,6‐lutidine in THF at 60 °C for 3 h was developed in one step, in which a copper(I)‐catalyzed 1,3‐dipolar cycloaddition, ketenimine formation, and 6π‐electrocyclization followed by [1,3]‐H shift tandem reaction took place. This method enabled efficient synthesis of a wide range of 1‐aminonaphthalene and 3‐aminobenzofuran and 3‐aminobenzothiophene derivatives with the release of molecular nitrogen.

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“…ATP binding site is a hydrophobic pocket of p38a formed by residues VAL38, ALA51, HIS107, LEU108, MET109, and LEU167 [23]. In addition, hydrogen bond interactions of inhibitors with GLU71, MET109, ASP168 are extensively adopted in drug design [23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38α by molecular dynamics simulations and free energy calculations

Chen

Cui

2009

J Comput Aided Mol Des

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4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazines have been discovered as inhibitors of p38alpha. Experimental assays have proven that the configuration of alpha-Me-benzyl connected with amide at C6 is essential for the binding affinity. The S-configured inhibitor (11j) displays 80 times more potency than the R-configured one (11k). Here we investigated the mechanism how different configurations influence the binding affinity using molecular dynamics simulations, free energy calculations and free energy decomposition analysis. We found that the van der Waals interactions play the most important role in differentiating the activities between 11j and 11k with p38alpha. The difference of the van der Waals interactions is primarily determined by two residues, LEU108 and LEU167. Consequently stabilization of pyrrolo[2,1-f][1,2,4]triazine ring is important for the activities of inhibitors. Meanwhile we observed that the different configuration of the alpha-Me-benzyl group leads to the difference of binding between 11j and 11k. In conclusion, our work shows that it is feasible to analyze the chirality effect of inhibitors with different configurations by molecular dynamics simulations and free energy calculations, and provides useful information for drug design.

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Discovery and Optimization of p38 Inhibitors via Computer-Assisted Drug Design

Abstract: Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.

Cited by 25 publications

References 19 publications

Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Copper(I)‐catalyzed Cyclization Reactions of Ethyl (E)‐α‐Ethynyl‐β‐Aryl‐α,β‐Unsaturated Esters with N‐Sulfonyl Azides: Synthesis of 1‐Aminonaphthalene, 3‐Aminobenzofuran, and 3‐Aminothiobenzofuran Derivatives

Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38α by molecular dynamics simulations and free energy calculations

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