C. Blair Zartman

Efficient synthesis of substituted piperazinones via tandem reductive amination–cyclization

Abstract A new strategy for the preparation of substituted piperazinones features a tandem reductive coupling and S N 2-cyclization of a 2-chloro- N -(2-oxoalkyl)acetamide ( 1 ) and a primary amine ( 2) . The method is convenient for diversity-oriented synthesis, since a wide variety of amines may be used in the ring-forming reaction to produce N -substituted piperazinones ( 3 ).

MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2-oxo-1,2,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.

Oxo-piperazine Derivatives of N-Arylpiperazinones as Inhibitors of Farnesyltransferase

The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmacokinetic profile relative to the parent 1-aryl-2-piperazinones.

[(11)C]MK-4232: The First Positron Emission Tomography Tracer for the Calcitonin Gene-Related Peptide Receptor.

Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.

Arylmethanesulfonates are convenient latent phenols in the nucleophilic aromatic substitution reaction

Abstract The methanesulfonyl protecting group for a phenol is conveniently unmasked under the conditions of the S N Ar reaction with an activated aryl halide, producing diarylether products directly. The method is advantageous when the preparation of a phenol substrate requires O -protection, since the selection of the robust methanesulfonate as a latent phenol obviates a deprotection step prior to the S N Ar reaction.

The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists

A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.

Identification of a novel RAMP-independent CGRP receptor antagonist.

Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site.

Substituted alkylpyridines as P3′ ligands for the hydroxyethylpiperazine class of HIV-1 protease inhibitors: Improved pharmacokinetic profiles

Abstract As a systematic approach to develop HIV-1 protease inhibitors exhibiting desirable pharmacokinetic profiles, hydroxyethylpiperazine series of inhibitors containing various mono- or dialkyl-substituted pyridylmethyl groups have been examined. Very high enzyme inhibitory potency and antiviral activity in a whole cell assay were observed with these inhibitors and, when administered orally to dogs, selected compounds in this series exhibited prolonged half-lives compared to the non-substituted pyridylmethyl compound 1 .