James B. Doherty

Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase.

The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).

p38MAP kinase inhibitors. Part 1: design and development of a new class of potent and highly selective inhibitors based on 3,4-dihydropyrido[3,2-d]pyrimidone scaffold.

A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine scaffold has been developed. These inhibitors exhibit unprecedented selectivity towards p38 over other very closely related kinases. Compounds 25, 33, and 34 were identified as benchmark analogues for follow-up studies. They show good potency for enzyme inhibition and excellent functional activity.

PMN elastases: A comparison of the specificity of human isozymes and the enzyme from other species toward substrates and inhibitors

The human elastases isolated from polymorphonuclear neutrophils (PMN) and purulent sputum displayed identical kinetic constants toward substrates and inhibitors. The elastases from the two sources yield identical N-terminal sequences and were recognized by antiserum prepared against human sputum elastase (HSE) isozyme-4 (I-4). The data support the proposal put forth by Twumasi and Liener (1977, J. Biol. Chem. 252, 1917-1926) that the human elastase from sputum is of PMN origin. PMN elastases from other species displayed kinetic constants toward both substrates and inhibitors significantly different from the human enzyme. Therefore, extrapolation of inhibitor profiles from these elastases to the human source should be avoided. Four groups of isozymes were resolved from HSE by FPLC. Only the most basic isozyme (I-4) was obtained as a single species. The isozymes displayed identical macroscopic kinetic constants toward several substrates and two classes of inhibitors. The similar partition ratios observed with a cephalosporin-derived inhibitor suggest that the microscopic rate constants are also identical. The data support the proposal suggested by Baugh and Travis (1976, Biochemistry 15, 836-841) that HLE isozymes differ only in carbohydrate content. Whatever the source of human PMN elastase heterogeneity, it does not result in heterogeneous catalytic properties. In addition, a new protein was identified in elastase preparations derived from human sputum. This protein displayed homology to serine proteases and properties suggesting that it is identical to azurocidin.

Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors.

Synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and lead to enhanced p38 inhibitory activity. From a study of C-7 substitutions by amino acid side chains, a very potent series of compounds in the p38 enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity can be improved in this series of compounds by judicious modification of the physical properties at appropriate regions of the lead.

Prevention of human leukocyte elastase-mediated lung damage by 3-alkyl-4-azetidinones

Abstract Simple 3-alkyl-4-azetidinones have been previously reported as potent inhibitors of human leukocyte elastase (HLE). Further modification of these simple monocyclic β-lactams has led to development of substituted 4-azetidinones that both inhibit HLE in a time dependent manner and, like previously reported modified cephalosporin sulfones, prevent HLE-induced lung damage in hamsters.

Inhibition of human leukocyte elastase by C-2 substituted cephalosporin sulfones

Abstract Cephalosporin sulfones with a number of substituents at the C-2 position were prepared and tested as inhibitors of human leukocyte elastase (HLE), an enzyme implicated in the tissue destruction associated with pulmonary emphysema. Nearly all substituents gave a substantial increase in activity against the enzyme over the unsubstituted parent. The enzyme can accommodate a number of functional groups at this position, but is not very discriminating. Both α- and β-methyl compounds have comparable activity, as do α-phenylthiomethyl and α-methoxy. Substitution at this position has led to the preparation of several compounds with exceptional potency against HLE.

Inhibition of human leukocyte elastase. 6. Inhibition by 6-substituted penicillin esters.

Abstract Penicillin amides substituted at C-6 with either an α- or β-trifluoroacetamido or an α-alkoxy functionality are reported as human leukocyte elastase (HLE) inhibitors. The structure activity relations for these derivatives are discussed and compared to the corresponding known cephalosporin structures in terms of chemical stability, HLE inhibition, and efficacy in an intratracheal (IT) lung hemorrhage assay.

Inhibition of human leukocyte elastase. 5. Inhibition by 6-alkyl substituted penem benzyl esters.

Abstract Penem benzyl esters substituted at the 6-position with small alkyl groups and at the 3-position with a variety of carbon and heteroatom groups were prepared as inhibitors of human leukocyte elastase (HLE). The structure activity relations found for these positions are discussed in relation to know cephalosporin inhibitors and some important stereochemical implications are reported for inhibition of HLE by these β-lactam structures.

Synthesis and biological activity of pyridopyridazin-6-one p38 MAP kinase inhibitors. Part 1.

This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24h coverage in the rat arthritis efficacy model.

The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastase

Abstract Substituted monocyclic β-lactam have recently been reported as inhibitors of human leukocyte elastase (HLE). Simple N-acetyl-2-azetidinone lead structures were found to undergo N-deacylation as well as β-lactam ring opening. The development of the N-carbamoyl-2-azetidinone nucleus was crucial to the stability of these compounds for effective oral bioavailability.