No abstract

Modification of the standard recession of the inferior oblique muscle for overacting inferior obliques has been performed by the authors. The inferior oblique has been detached from the globe as in the usual recession procedure, but has been reattached slightly anterior to the temporal border of the insertion of the inferior rectus. The results in 64 anterior transpositions are compared to the results in 90 standard recessions varying from 8 to 14 mm in magnitude. Our analysis shows that anterior transposition appears to be an effective procedure in eliminating inferior oblique overaction. It also produced excellent results in seven cases in which inferior oblique overaction persisted following previous standard recessions. This procedure appears to have excellent applicability in persistent and, possibly, marked cases of overaction of the inferior oblique.

Cross-conjugated dienone 18, a known precursor to (±)-coriolin, is prepared in 13 steps from simple lactone 4. Selective epoxidation of 18 provides (±)-hypnophilin. Key steps in the synthesis of 18 include a highly efficient SN2'-anti opening of 4 to give the necessary trans-3,5-disubstituted cyclopentene 11 and the novel Sml2-induced tandem radical cyclization of aldehyde 14.

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.