Design and synthesis of polyethylene glycol-modified biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.

Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.

1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists.

A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRbeta binding IC(50) values <10nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.

Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists.

A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.

4-(3-Aryloxyaryl)quinoline sulfones are potent liver X receptor agonists.

A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.

Biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.

Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.

Design and Enantioselective Synthesis of a Peptidomimetic of the Turn in the Helix-Turn-Helix DNA-Binding Protein Motif.

A peptidomimetic of the turn in the helix-turn-helix (HTH) motif of DNA-binding proteins was designed and synthesized. Conformational constraint was achieved by an unusual linking of two amino acids with a side chain carbon-carbon bond. A phenyl ring provides the potential for new hydrophobic contacts with the hydrophobic core of the HTH motif. In the mimic, the peptide backbone and the central residue were retained in native form within a 12-membered cyclic tripeptide. The target compound 1b was synthesized by two sequential Horner-Wittig couplings followed by enantioselective hydrogenation with Rh(MeDuPHOS) in eight steps and 35% overall yield. The stereochemical outcome of the key hydrogenation was determined by aromatic ring oxidation with RuO(2)/NaIO(4) to give 2 equiv of Boc-Asp-OMe.

Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo.

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s.

Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.