The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck).

This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases).

The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lymphocyte specific kinase (Lck).

This communication details the synthesis, biological activity, and proposed binding mode of a novel class of tri-cyclic derivatives of 1,2-dihydro-pyrimido[4,5-c]pyridazines 1 and 2. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase.

The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-alpha production.

A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).

Development of N-4,6-pyrimidine-N-alkyl-N'-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase.

A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study.

Development of N-2,4-pyrimidine-N-phenyl-N'-alkyl ureas as orally active inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 2.

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.

Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1.

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.

The development of monocyclic pyrazolone based cytokine synthesis inhibitors.

4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.

The development of new isoxazolone based inhibitors of tumor necrosis factor-alpha (TNF-alpha) production.

4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.

The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.

4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.

The development of novel inhibitors of tumor necrosis factor-alpha (TNF-alpha) production based on substituted [5,5]-bicyclic pyrazolones.

Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.

Development of orally bioavailable bicyclic pyrazolones as inhibitors of tumor necrosis factor-alpha production.

2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.

The development of new triazole based inhibitors of tumor necrosis factor-alpha (TNF-alpha) production.

4-Aryl-5-pyridyl and 4-aryl-5-pyrimidyl based inhibitors of TNF-alpha production, which contain a novel triazole 5-member heterocyclic core, are described. Many pyridyl triazoles containing either an alkyl ether or a substituted aryl side chain on the triazole core showed sub-micromolar activity against LPS-induced TNF-alpha, while pyrimidyl triazoles containing an ethoxymethyl side chain exhibited even better inhibitory activity. Secondary screening data are presented for the pyrimidyl triazoles. Triazole 14e combined excellent potency with good oral bioavailability in the rat.