Gunnar J. Hanson

Inhibitors of p38 kinase

Inhibition of p38 kinase is evolving as an approach to the discovery of new anti-inflammatory agents. Inhibitors of this enzyme modulate cytokine production, especially pro-inflammatory TNF-α and IL-1. These cytokines and others mediate a wide spectrum of diseases, notably rheumatoid arthritis. Cytokine modulators are expected to be disease modifying agents. The lead molecules disclosed in the patent literature fall into a class termed 1-pyridinyl-2-phenylazoles; this class of compounds encompasses promising drug candidates that are non-peptide, orally active, of low molecular weight and selective for p38. Structural characteristics of inhibitors and p38 kinase background are discussed.

Stereoselective addition of lithioethyl acetate to Boc-L-prolinal. A convenient chiral synthetic building block for the pyrrolizidine alkaloid ring system

Abstract Aldol condensation of lithioethyl acetate with Boc- lfsf -prolinal proceeds stereoselectively to give R,S diastereomer 2. Acidolysis of the Boc group and lactamization gives crystalline 3 which possesses the pyrrolizidine alkaloid skeleton. Saponification and acidolysis of 2 yields 7, a novel GABA analogue.

A new class of orally active glycol renin inhibitors containing phenyllactic acid at P3.

We prepared a new series of renin inhibitors based on dipeptide glycols, replacing the P4-P3 subsites with an O-(N-morpholinocarbonyl)-3-L-phenyllactic acid residue. This modification proved bioisosteric with Boc-L-phenylalanine, giving rise to highly potent human renin inhibitors (1-5 nM), e.g., SC-46944 (IC50 = 5 nM). Moreover, this change produced compounds that are orally efficacious in reducing plasma renin activity in salt-depleted marmosets.

Stereoselective Δ4-pipecolic acid synthesis via alkylation of a vinyl N-Boc-iminium ion derived from Baikiain

Stereoselective functionalization of Boc-(±)-Baikian was demonstrated via seleno- and iodolactonization to afford lactones 5. These were converted to enecarbamate 7, which undergoes regio- and stereoselective alkylation at C-6 upon treatment with organoaluminum reagents.

Dipeptide glycols: A new class of renin inhibitors

The discovery of a new class of novel renin inhibitors consisting of protected dipeptide amides derived from aminoglycols (Formula I) prompted a study of structure-activity in vitro and efficacy in vivo. Thus, Boc-L-Phe-N-[(1S,2R)-1-benzyl-(2,3-dihydroxy)propyl]-L-leucinamide (1) and the corresponding histidinamide (2) inhibit human renin in vitro (IC50: 8.7 X 10-6 M and 2.6 X 10-6 M, respectively). Compound 1 has a slight inhibitory effect on pepsin and compound 2 does not inhibit pepsin at all (at 10-4M); these compounds are inactive against rat renin. Compound 1 is efficacious in lowering plasma renin activity in the Rhesus monkey (i.v.). Results indicate that this new class of low molecular weight inhibitors is specific for human renin and thus constitutes a new source of drug candidates.

Design of MHC class II (DR4) ligands using conformationally restricted imino acids at p3 and p5

High potency synthetic ligands were designed for rheumatoid arthritis linked Class II MHC, DR4 Dw4. The design strategy utilized isosteric replacements at the p1 and p7 positions and conformational restriction with imino acids pipecolic acid (Pec) and proline at the solvent exposed residues p3 and p5. In particular, SC-67655, (S)-CBA-Val-Pec-Asp-Pro-Thr-NH-n-Pr (IC50 = 50 nM) is a potent and stable pentapeptide DR4 ligand.

Enhanced potency dipeptide glycol renin inhibitors: Studies in vitro and in the conscious rhesus

We prepared a series of novel dipeptide amides of the formula Boc-Phe-Leu-X, where X is a 3-amino-3-alkyl-1,2-propanediol with lower alkyl substitutions at C-1, in order to probe accessory binding sites in the enzyme renin. This approach was successful in generating potent inhibitors of human and hog renin in vitro. Moreover, these inhibitors were able to effect in vivo reduction of plasma renin activity (PRA) in the conscious salt-depleted rhesus monkey (i.v. route); this effect was related to the size of the C-1 alkyl group.

Effects of SC-56525, a Potent, Orally Active Renin Inhibitor, in Salt-Depleted and Renal Hypertensive Dogs

SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.