Horng-Chih Huang

Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy

We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.

Diaryl indenes and benzofurans: Novel classes of potent and selective cyclooxygenase-2 inhibitors

Abstract Novel series of diaryl indenes and benzofurans have been shown to be potent and selective COX-2 inhibitors. A structure-activity relationship study suggests that the conversion of sulfones to sulfonamides affords potent, but slightly less selective COX-2 inhibitors, and that for benzofurans the 3-halo-4-methoxyphenyl sulfonamide analogs are more selective than the corresponding 4-fluorophenyl analog.

Stereochemical Requirements for the Mineralocorticoid Receptor Antagonist Activity of Dihydropyridines

A number of known 1,4-dihydropyridine CCBs were identified as having comparable potency to the steroidal MR antagonist eplerenone. Chiral resolution of mebudipine revealed that MR and CCB activity reside in opposite enantiomers. Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine. Molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters.

Discovery of Novel Cyanodihydropyridines as Potent Mineralocorticoid Receptor Antagonists

A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.

A novel one-pot conversion of methyl sulfones to sulfonamides

Abstract A one-pot synthesis of sulfonamides from methyl sulfones has been developed. Treatment of methyl sulfones with base and trialkylboranes gave the corresponding rearranged sulfinic acid salts which were converted to sulfonamides during oxidative-amination workup.

NEW DEVELOPMENTS IN THE USE OF ENANTIOMERICALLY ENRICHED SULFOXIDW IN STEREOSELECTIVE SYNTHESES

INTRODl CTION ............................................................................................................................... 27 . 1 . SYNHESIS OF ENANTIOMERICALLY ENRICHED SULFOXIDES ................................. 273 11 . CYCLOADDITION REACTIONS ............................................................................................. 277 1 . Diels-Alder Reactions .................................................................................................................. 277 2 . Hetero Diels-Alder Reactions ...................................................................................................... 282 3 . 1. 3.Dipolar Cycloaddition Reactions .......................................................................................... 283 111 . PUMMERER REACTIONS ....................................................................................................... 284 IV . NUCLEOPHILIC ADDITION REACTIONS OF SULFINYL CARBANIONS ................ 288 V . REDUCTION REACTIONS ........................................................................................................ 294 VI . NUCLEOPHILIC SUBSTITUTION REACTIONS ................................................................ 300 W . CYCLOPROPANATION REACTIONS ................................................................................. 302 VIII . EPOXIDATION REACTIONS ............................................................................................... 304 IX . RADICAL REACTIONS ............................................................................................................ 305 1 . Addition Reactions ....................................................................................................................... 305 2 . Cyclization Reactions ................................................................................................................... 307 X . PROTONATION REACTIONS .................................................................................................. 308 XI . MISCELLANEOUS REACTIONS ............................................................................................ 310 1 . Intramolecular Heck Reactions ................................................................................................... 310 2 . Intramolecular Pauson-Khand Reactions ................................................................................... 311 3 . Intramolecular Ene Reactions ..................................................................................................... 311 4 . Hydrocyanation Reactions ........................................................................................................... 312 XII . CONCLUSIONS ......................................................................................................................... 312 REFERENCES .................................................................................................................................... 313

Discovery of nonpeptide potent conformationally restricted angiotensin II receptor antagonists

Abstract A series of potent, selective, conformationally restricted angiotensin II (AII) receptor antagonists has been discovered. Two classes of conformationally restricted analogues were prepared: triazolone-based and imidazole-based biphenyl derivatives. The most active compound, an imidazole-based analogue, has an IC 50 of 11 nM and a pA 2 of 8.8.