Benzimidazolone p38 inhibitors

Dombroski, Mark A.; Letavic, Michael A.; McClure, Kim F.; Barberia, John T.; Carty, Thomas J.; Cortina, Santo R.; Csiki, Csilla; Dipesa, Alan; Elliott, Nancy C.; Gabel, Christopher A.; Jordan, Crystal K.; Labasi, Jeff M.; Martin, William H.; Peese, Kevin M.; Stock, Ingrid A.; Svensson, Linne; Sweeney, Francis J.; Yu, Chul H.

doi:10.1016/j.bmcl.2003.12.023

Cited by 34 publications

(29 citation statements)

References 25 publications

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“…Other recent structurally distinctive modifications to the original pyridylimidazole class include the replacement of the pyridyl or pyrimidyl groups with bicyclic heterocycles such as in the recently disclosed Eli Lilly compound 6 [26] and the Pfizer compounds 7 [27] and 8 [28], respectively, Fig. (6).…”

Section: Fig (5)mentioning

confidence: 99%

Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions

Wrobleski¹,

Doweyko²

2005

CTMC

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Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimer's disease, diabetes, and rheumatoid arthritis has attracted significant attention over the past two decades and has clearly become one of the most significant challenges for drug discovery in the 21st century. While the recent identification of 518 different kinases in the human genome has offered a wealth of opportunities for drug intervention in the treatment of these diseases, it has also created a daunting challenge with respect to selective kinase inhibition as a viable strategy in target-based drug design. Over the past decade, the design and development of a small molecule that selectively inhibits the p38 mitogen activated protein (MAP) kinase has clearly emerged as one of these challenges within the industry. This review will focus on the comparison of the x-ray crystal structures and binding models of the most recent p38 inhibitor-enzyme complexes and the identification of the structural elements and interactions that may be important in providing inhibitor potency and selectivity toward the p38 MAP kinase.

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Section: Fig (5)mentioning

confidence: 99%

Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions

Wrobleski¹,

Doweyko²

2005

CTMC

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“…The present work describes the preclinical pharmacokinetics of the novel p38 inhibitor 1 with in vitro and in vivo inhibitory potency comparable or superior to many of the previously described structurally diverse p38 inhibitors [5][6][7][8][9]. In addition, the results of the current analysis also established the favorable disposition properties of 1 in preclinical species.…”

Section: Discussionmentioning

confidence: 60%

Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine, a novel and selective p38α inhibitor: identification of an active metabolite in preclinical species and human liver microsomes

Kalgutkar¹,

Hatch²,

Kosea³

et al. 2006

Biopharm. Drug Dispos.

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The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38alpha, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vd(ss)) ranging from 0.4-1.3 l/kg (2.4-26 l/m(2)) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m(2)) and Sprague-Dawley rats (7.65+/-1.08 ml/min/kg, 45.9+/-6.48 ml/min/m(2) in male rats and 3.15+/-0.27 ml/min/kg, 18.9+/-1.62 ml/min/m(2) in female rats) and moderate in beagle dogs (12.3+/-5.1 ml/min/kg, 246+/-102 ml/min/m(2)) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30-65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38alpha in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (f(u) approximately 0.1-0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC(50)>50 microM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent.

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“…The majority of this effort focused on replacements of the imidazole core including furans [28], pyrroles [28], pyrazolones [28], indoles [29], pyrrolopyridines [29,30], thiazoles [15], oxazoles [15], pyridazine [31], pyrimidines [32], 4-azaindoles [33], imidazopyrimidines [34], bicyclic pyrazolones [35], imidazo-pyridines [36] and bicyclic pyrazoles [37]. Rather than focusing on the central imidazole as the best region to gain novelty, researchers at Pfizer incorporated novelty starting from the SKF86002 series by replacing the pyridine with a benzimidazolone [38]. As most of this large body of work has been extensively reviewed elsewhere [39,40], we will avoid doing so in any amount of detail.…”

Section: The Initial P38 Discoverymentioning

confidence: 98%

“…It is noteworthy that compound 31 inhibits TNFα production in PBMCs with an IC50 of 300 nM. Compound 32 was developed at Pfizer and has p38 IC50 of 140 nM [38].…”

Section: The Discovery Of P38 Chemotypes Via High Throughput Screeningmentioning

confidence: 99%

The Discovery of Novel Chemotypes of p38 Kinase Inhibitors

Diller¹,

Lin²,

Metzger³

2005

CTMC

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In the late 1970s and the early 1980s the initial p38 chemotype, the triaryl imidazoles, was discovered as an off-target effect during the development of cyclooxygenase and 5-lipoxygenase inhibitors long before the identity of the p38 kinase was known. During the last 10 years a number of novel p38 chemotypes were discovered via high throughput screening. More recently, the first series of p38 inhibitors discovered by xray crystallographic and virtual screening was announced. Finally, throughout the life span of p38 drug discovery programs significant medicinal chemistry effort has continually been placed on the design of new inhibitors from known chemotypes using molecular modeling, protein crystallography, hybrid design and simply sound intuition. Indeed, the search for p38 kinase inhibitors offers an excellent historical perspective as to how technological changes that have taken place in the pharmaceutical industry over the last decade, have affected the ways in which new leads are discovered and advanced. It is the intent of this review to highlight the discoveries of novel p38 chemotypes, emphasizing where possible the key technologies used in the discoveries and the knowledge gained from each discovery.

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Benzimidazolone p38 inhibitors

Cited by 34 publications

References 25 publications

Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions

Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions

Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine, a novel and selective p38α inhibitor: identification of an active metabolite in preclinical species and human liver microsomes

The Discovery of Novel Chemotypes of p38 Kinase Inhibitors

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