Discovery of an HIV integrase inhibitor with an excellent resistance profile

Discovery of an HIV integrase inhibitor with an excellent resistance profile

Med. Chem. Commun., 2013, Advance Article
DOI: 10.1039/C3MD00014A, Concise Article
David C. Pryde, Rob Webster, Scott L. Butler, Edward J. Murray, Kevin Whitby, Chris Pickford, Mike Westby, Michael J. Palmer, David J. Bull, Hannah Vuong, David C. Blakemore, Darren Stead, Christopher Ashcroft, Iain Gardner, Claire Bru, Wai-Yee Cheung, Ieuan O. Roberts, Jennifer Morton, Richard A. Bissell
PFIZER GLOBAL, KENT, UK
Structure-activity relationship studies within a series of N-hydroxy-dihydronaphthyridinone HIV integrase inhibitors led to a candidate compound, of high potency and with an excellent resistance profile.

In the present article, we describe SAR studies within a series of N-hydroxy-dihydronaphthyridinone HIV integrase inhibitors that led to a candidate compound, PF-4776548, of high potency and with an excellent resistance profile. Uncertainties around the human pharmacokinetic predictions for PF-4776548 led to the compound being taken into a human microdose study to confirm its human pharmacokinetics, the results of which are described herein.

Graphical abstract: Discovery of an HIV integrase inhibitor with an excellent resistance profile
DOI: 10.1039/C3MD00014A

Identification of 4,6-diaryl-1,4-dihydropyridines as a new class of neuroprotective agents

Identification of 4,6-diaryl-1,4-dihydropyridines as a new class of neuroprotective agents

Med. Chem. Commun., 2013, 4,590-594
DOI: 10.1039/C3MD20345J, Concise Article
Giammarco Tenti, Javier Egea, Mercedes Villarroya, Rafael Leon, Jose Carlos Fernandez, Juan Fernando Padin, Vellaisamy Sridharan, M a Teresa Ramos, J. Carlos Menendez
MADRID SPAIN
4,6-Diaryl-1,4-dihydropyridines, lacking the structural features needed for vascular activity, were found to prevent calcium overload and behave as neuroprotective agents.

A library of 4,6-diaryl-1,4-dihydropyridines was synthesized using a CAN-catalyzed, Hantzsch-related three component reaction starting from ammonium acetate, β-dicarbonyl compounds and a variety of α,β-unsaturated ketones including chalcones, their vinylogs and heteroanalogues. These compounds lack the structural features needed for vascular activity and were found to prevent calcium overload and behave as neuroprotective agents. One of the compounds, bearing a 2-thienyl substituent at C-4, showed the highest neuroprotective activity and was also a moderate antioxidant, being a good lead compound for further studies in this area.

Graphical abstract: Identification of 4,6-diaryl-1,4-dihydropyridines as a new class of neuroprotective agents

Stereoselective approaches to amides from chiral alcohols

thumbnail image: New Route to Chiral Amides

A Direct and Stereoretentive Synthesis of Amides from Cyclic Alcohols
D. Mondal, L. Bellucci, S. D. Lepore,
Eur. J. Org. Chem. 2011.
DOI: 10.1002/ejoc.201101165

Salvatore Lepore and colleagues, Florida Atlantic University, USA, report a one-pot amidation reaction for cyclic alcohols that gives complete retention of configuration. They use a chlorosulfite leaving group formed in situ by reaction of the alcohol and thionyl chloride. The leaving group is chelated by a TiIV nitrile complex that is also generated in situ by reaction of TiF4 and alkyl or aryl nitrile.

One-pot, stereoretentive amidation of alcohols

The Ti nitrile complex is thought to chelate the chlorosulfite in the transition state to create a carbocation that is rapidly captured by the nitrile nucleophile through a front-side attack mechanism. This is the first experimental verification of secondary hyperconjomers, a theory of non-planar carbocations developed by Sorensen and Schleyer.

Most stereoselective approaches to amides from chiral alcohols require multistep procedures.

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DR ANTHONY CRASTO

SN1 REACTION, STEREOCHEMISTRY

Stereochemistry

The carbocation intermediate formed in the reaction’s rate limiting step is an sp2 hybridized carbon with trigonal planar molecular geometry. This allows two different avenues for the nucleophilic attack, one on either side of the planar molecule. If neither avenue is preferentially favored, these two avenues occur equally, yielding a racemic mix of enantiomers if the reaction takes place at a stereocenter.This is illustrated below in the SN1 reaction of S-3-chloro-3-methylhexane with an iodide ion, which yields a racemic mixture of 3-iodo-3-methylhexane:

A typical SN1 reaction, showing how racemisation occurs

However, an excess of one stereoisomer can be observed, as the leaving group can remain in proximity to the carbocation intermediate for a short time and block nucleophilic attack. This stands in contrast to the SN2 mechanism, which is a stereospecific mechanism where stereochemistry is always inverted.

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