The discovery and SAR of cyclopenta[b]furans as inhibitors of CCR2.

The discovery of a novel series of cyclopenta[b]furans as CCR2 inhibitors is discussed. This series has excellent CCR2 potency and PK characteristics, and good cardiovascular safety.

Novel 2-aminooctahydrocyclopentalene-3a-carboxamides as potent CCR2 antagonists.

Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.

The discovery of novel cyclohexylamide CCR2 antagonists.

As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.

Direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes via Pd/Cu-catalyzed phosphonium coupling.

The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp(2))-C(sp) bond formation, which is in line with ideal synthesis using readily available materials.

Pd-catalyzed direct arylation of tautomerizable heterocycles with aryl boronic acids via C-OH bond activation using phosphonium salts.

The first direct arylation via C-OH bond activation of tautomerizable heterocycles has been achieved using phosphonium salts, on the basis of a combination of the phosphonium coupling and Suzuki-Miyaura cross-coupling conditions. Optimal reaction condition is obtained through screening of phosphonium salts, Pd catalysts, and bases. The direct arylation via C-OH bond activation tolerates a variety of tautomerizable heterocycles and aryl boronic acids. The mechanism of the Pd-catalyzed phosphonium coupling is proposed to proceed via a domino seven-step process including the unprecedented heterocycle-Pd(II)-phosphonium species. Application of the Pd-catalyzed direct arylation via C-OH bond activation using PyBroP leads to the most efficient synthesis of the biologically important 6-arylpurine ribonucleoside in a single step from unactivated and unprotected inosine.

Insight from molecular modeling into different conformation and SAR of natural steroids and unnatural 7-oxa-steroids.

Replacement of the 7-CH2 group of natural steroid with an oxygen atom led to identification of unnatural 7-oxa-steroids as potent and selective progesterone receptor antagonists. The unnatural 7-oxa-steroids exhibited a different structure-activity relationship (SAR) from natural steroids. Molecular modeling demonstrated that the switch of carbon to oxygen in the B-ring results in a subtle conformational change of the tetracyclic skeleton and induces a remarkable spatial shift at the terminal end of the side chain of the D-ring. This shift causes the phenyl ring on the D-ring to form a perfect parallel-displaced form of pi-pi interaction with the phenyl ring of Phe794. The unnatural 7-oxa-steroids were orally active in a rat complement C3 assay and showed comparable pharmacokinetic and metabolic profiles to those of the natural steroid, mifepristone.

Parallel synthesis and SAR study of novel oxa-steroids as potent and selective progesterone receptor antagonists.

Efficient parallel synthesis of novel 7-oxa-steroids 4 has been achieved from the key intermediate 3 via a one-pot four-step sequence. oxa-Steroids 4 with various ortho-, meta-, and para-monosubstituents on the phenyl ring, as well as disubstituted phenyl and heterocycles, were evaluated for progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist activities. SAR study demonstrated that the para-fluorinated substituents on the phenyl ring not only increased the potency for PR in a T47D cell functional assay, but also improved the selectivity over GR in an A549 cell functional assay. The para-fluorophenyl oxa-steroid 4l and the para-trifluoromethylphenyl oxa-steroid 4p were found to be remarkably more potent and more selective PR antagonists than mifepristone, with subnanomolar potency and about 140-fold selectivity over GR. Molecular modeling of the oxa-steroid bound to PR provided meaningful insight for the SAR study. oxa-Steroids 4a and 4b were found to be more efficacious than mifepristone in vivo in a rat uterine complement C3 assay via the oral route, although they were less than or equally potent to mifepristone in the T47D assay.

Synthesis and identification of novel oxa-steroids as progesterone receptor antagonists.

A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR.

Efficient conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-one to pyrimidines via PyBroP-mediated coupling.

An efficient two-step procedure is described to convert the Biginelli 3,4-dihydropyrimidin-2(1H)-one to various multifunctionalized pyrimidines via the Kappe dehydrogenation and a new mild PyBroP-mediated coupling with C, N, O, and S nucleophiles, which provides a readily accessible multifunctionalized pyrimidine template for diversity-oriented synthesis.

Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: stoichiometric process.

[reaction: see text] Via an X-ray analysis, the sulfonamide bearing R(1) = i-Pr, R(2) = Me, and R(3) = Me is shown to be a tridentate ligand to a Cr(III) salt. This class of ligands, represented by R(1) = t-Bu, R(2) = 2-naphthyl, and R(3) = Me, is effective to achieve an asymmetric Ni/Cr-mediated coupling reaction and, with the C14-C38 segment of halichondrins, its synthetic potential has been demonstrated. A possible mechanism is suggested for the process.

Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: catalytic process.

[reaction: see text] The stable, crystalline Cr(III)/sulfonamide complex 1a is shown to be an effective catalyst for the Ni/Cr-mediated coupling reaction. A possible mechanism is suggested for the process. 1a is also effective for other Cr-mediated coupling reactions. With this catalyst, a concise and efficient synthesis of the C14-C26 segment of halichondrins has been developed.