Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia.

Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.

Enantiomerically pure rhodium complexes bearing 1,5-diphenyl-1,5-cyclooctadiene as a chiral diene ligand. Their use as catalysts for asymmetric 1,4-addition of phenylzinc chloride.

[reaction and structures: see text] A rhodium complex coordinated with 1,5-diphenyl-1,5-cyclooctadiene (Ph-cod), [RhCl((R)-Ph-cod)]2, was obtained enantiomerically pure through optical resolution of diastereomeric isomers [Rh(Ph-cod)((R)-1,1'-binaphthyl-2,2'-diamine)]BF4. The enantiomerically pure rhodium complexes showed high catalytic activity and enantioselectivity (up to 98% ee) in the asymmetric 1,4-addition of phenylzinc chloride to alpha,beta-unsaturated ketones and esters in the presence of chlorotrimethylsilane.

Catalytic asymmetric arylative cyclization of alkynals: phosphine-free rhodium/diene complexes as efficient catalysts.

Catalytic arylative cyclization of alkynals has been developed by the use of phosphine-free rhodium/diene complexes as catalysts. An asymmetric variant of this process has been successfully realized by employing a C2-symmetric chiral bicyclo[2.2.2]octadiene ligand. The rhodium/diene catalyst system is also effective for arylative cyclization of other substrates such as alkynones and enynes, achieving multiple carbon-carbon bond formations in a single step.

C2-symmetric bicyclo[2.2.2]octadienes as chiral ligands: their high performance in rhodium-catalyzed asymmetric arylation of N-tosylarylimines.

Asymmetric synthesis of diarylmethylamines with high enantioselectivity (95-99% ee) was realized by use of a new C2-symmetric diene ligand, (1R,4R)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene (Ph-bod*), for the rhodium-catalyzed asymmetric arylation of N-tosylarylimines with arylboroxines.

Chiral norbornadienes as efficient ligands for the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds.

[reaction: see text] A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds has been developed. While phosphorus-based chiral ligands fail to induce high stereoselectivity, chiral norbornadiene ligands have proved to be uniquely effective to achieve high enantioselectivity in these 1,4-addition reactions.

A chiral chelating diene as a new type of chiral ligand for transition metal catalysts: its preparation and use for the rhodium-catalyzed asymmetric 1,4-addition.

As a new type of chiral ligand, a C2-symmetric norbornadiene derivative (1R,4R)-2,5-dibenzylbicyclo[2.2.1]hepta-2,5-diene (1) was prepared and used for the rhodium-catalyzed asymmetric addition of organoboron and -tin reagents to alpha,beta-unsaturated ketones, which gave high yields of the 1,4-addition products with up to 99% enantioselectivity.

Palladium-catalyzed asymmetric synthesis of axially chiral (allenylmethyl)silanes and chirality transfer to stereogenic carbon centers in S(E)' reactions.

[reaction: see text] Novel stereoselective reactions of 4-substituted-1-trimethylsilyl-2,3-butadienes ((allenylmethyl)silanes) were developed. The axially chiral (allenylmethyl)silanes were prepared from (3-bromopenta-2,4-dienyl)trimethylsilane by a Pd-catalyzed asymmetric reaction with soft nucleophiles with up to 88% enantioselectivity. The (allenylmethyl)silanes reacted with acetals in the presence of a TiCl(4) promoter to give 1,3-diene derivatives via an S(E)' pathway. The 1,3-dienyl products have (E)-geometry exclusively and up to 88%( )()chirality transfer from the axially chiral allenes to the centrally chiral 1,3-dienes was observed in the S(E)' reaction.