Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors.

Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.

Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists.

Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties.

Diastereoselective one-pot Knoevenagel condensation/Corey-Chaykovsky cyclopropanation.

Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.

Small molecules targeting sodium and calcium channels for neuropathic pain.

Neuropathic pain is a chronic disease, which impacts millions of individuals worldwide. The condition is currently treated with several drugs that provide pain relief that is inconsistent and complicated by CNS or cardiovascular (CV) side effects. Voltage-gated sodium channels (VGSCs) and voltage-gated calcium channels (VGCCs) are of particular interest as targets for neuropathic pain because they control electrical signals in both the central and peripheral nervous system. Recent research has demonstrated that the expression of voltage-gated ion channels changes significantly under conditions of neuropathic pain in rodents and humans. Selective modulation of the channels involved in the pathology of the disease, while sparing the channels that are essential for normal nociception, offers promising opportunities for therapeutic intervention. This review summarizes recent developments of small molecules that target VGSCs and VGCCs.

N-phenylphenylglycines as novel corticotropin releasing factor receptor antagonists.

Screening of a computationally designed synthetic library led to the discovery of the N-phenylphenylglycines (NPPGs) as a novel class of human corticotropin releasing factor (h-CRF(1)) antagonists. Several NPPGs with greater potency than the original hit 1 were rapidly identified, and resolution of the racemate demonstrated that only the R-enantiomer displays activity. This structural class represents the first example of a non-peptide CRF(1) antagonist with a stereochemically distinct receptor binding affinity.

Arylamidrazones as novel corticotropin releasing factor receptor antagonists.

The arylamidrazones have been found to be potent corticotropin releasing factor (CRF) receptor antagonists structurally distinct from previously reported CRF1 antagonists. Attempts to modify the arylamidrazone core suggested an important role for the anilino NH moiety. The right-hand-side 2-nitro feature in lead 1 could be replaced with substituents methyl, chloro, cyano, or trifluoromethyl with a 4- to 10-fold reduction in receptor binding. With appropriate left-hand-side modifications, this potency loss could be recovered.