Chris Allen Broka

Amino acid derived sulfonamide hydroxamates as inhibitors of procollagen C-proteinase. Part 2: Solid-phase optimization of side chains

Optimization of the amino acid side chain and the N-alkyl group of the sulfonamide of amino acid derived sulfonamide hydroxamates is discussed. The solid-phase synthesis of these potent inhibitors of procollagen C-proteinase (PCP) is presented. In addition, novel carboxylic acid sulfonamides were discovered to be PCP inhibitors.

2-aryl-indolyl maleimides - novel and potent inhibitors of protein kinase C

Abstract A new class of protein kinase C (PKC) inhibitors is described. These inhibitors were derived from the familiar bis-indolyl maleimide series of inhibitors through a structural rearrangement involving transfer of one aryl ring from the maleimide moiety to the C-2 position of the indole ring remaining attached to that moiety. The resulting compounds are among the most potent known inhibitors of PKC and also show good selectivity for PKC in relation to other kinases. The lead compound in this series possesses antitumor activity in several in vitro and in vivo models.

A novel series of IKKβ inhibitors part I: Initial SAR studies of a HTS hit.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

A novel series of IKKβ inhibitors part II: description of a potent and pharmacologically active series of analogs.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.