Bruce L. Banner

Synthesis of optically active leukotriene (SRS-A) intermediates

Abstract In an approach to SRS-A and analogues thereof, the key (5 S , 6 S )-epoxy alcohol 9 and its 6-epimer 18 were prepared starting from D -araboascorbic acid and L -diethyl tartrate, respectively.

Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β agonist in clinical trials for the treatment of dyslipidemia.

The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: novel and highly selective protein tyrosine phosphatase 1B inhibitors.

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.

Potent, selective MCH-1 receptor antagonists.

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

An Asymmetric Total Synthesis of D-Homo Steroids Involving a Lewis Acid Directed Diels-Alder Reaction

Abstract In recent years, applications of asymmetric, amino acid mediated aldol cyclizations1,2 have led to major advances in steroid total synthesis.3 Typical of such processes is the conversion of prochiral triketone la 4 to the steroid CD-synthon, (S)-(+)-enedione 2a in high chemical and optical yield, under the influence of (S)- proline.1,2 This approach to the introduction of chirality is the foundation upon which several enantiospecific and highly efficient syntheses of biologically important steroids (19-norsteroids, A-ring aromatic steroids, androstanes) or their precursors are based.3

New results in the total synthesis of 19-norsteroids

Abstract Recent endeavors in the field of steroid total synthesis have led to several new approaches which utilize the principle of asymmetric induction. Important developments will briefly be reviewed, followed by a presentation of two novel routes to estrone. The first is based on the use of (—)-(5S)-5-hydroxy-9-oxodecanoic acid lactone which is transformed in several steps to d-(−)-estra-4.9-diene-3, 17-dione and thence to estrone. The second, altogether different route starts with (+)-(7aS)-7,7a-dihydro7a-methyl-1,5(6H)-indandione and involves the preparation of a 9,10- seco ACD-tricyclic intermediate and its conversion into d-(+)-estrone methyl ether.

NEW RESULTS IN THE TOTAL SYNTHESIS OF 19-NORSTEROIDS

Recent endeavors in the field of steroid total synthesis have led to several new approaches which utilize the principle of asymmetric induction. Important developments will briefly be reviewed, followed by a presentation of two novel routes to estrone. The first is based on the use of (—)-(5S)-5-hydroxy-9-oxodecanoic acid lactone which is transformed in several steps to d-(—)-estra-4,9-diene-3,17-dione and thence to estrone. The second, altogether different route starts with (+)-(7aS)-7,7a-dihydro-7a-methyl-1,5(6H)-indandione and involves the preparation of a 9,10-seco ACD-tricyclic intermediate and its conversion into d-(+)-estrone methyl ether.