Joseph P. Vacca

Clinically effective HIV-1 protease inhibitors

For 10 years now, the HIV-1 protease has been recognized as an attractive target for antiviral therapy, and the discovery of potent inhibitors has been the focus of many research groups. There are currently four HIV protease inhibitors approved in the USA for use in treating AIDS, and several compounds are in various phases of clinical development. All of these compounds represent important advances and result from intensive research efforts. This review outlines the approaches taken by the research groups in discovering their clinical compounds, the problems encountered during this process and their subsequent solutions. Limited clinical data are also presented for each compound.

L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor

Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.

New advances in the discovery of thrombin and factor Xa inhibitors

The search for the ideal anticoagulant has spanned decades and has resulted in several strategies including the clinical use of heparin, low molecular weight heparins, and the vitamin K antagonist warfarin. Over the past five years, many groups have reported preclinical results with direct-acting thrombin inhibitors and several of these are now moving into clinical trials. In addition, many groups have disclosed the discovery of potent, orally bioavailable factor Xa inhibitors. Several of these compounds are now in early clinical trials and the results are forthcoming.

The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations.

Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations.

L-373,890, an achiral, noncovalent, subnanomolar thrombin inhibitor

Abstract L-373,890, a highly selective and efficacious pyridinone acetamide thrombin inhibitor was designed using a combination of X-ray crystallography, molecular modeling and empirical structure optimization.

Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides.

In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.

Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position.

Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.

Design and Synthesis of 2,3,5-Substituted Imidazolidin-4-one Inhibitors of BACE-1

Alzheimer’s disease is a slowly progressing neurodegenerative condition that is increasing in prevalence because of the ageing population and is a significant healthcare burden. Although the pathophysiology of the disease has not been completely elucidated, abnormal production and/or clearance of a small peptide called Ab has been implicated from genetic and other studies. The Ab peptide arises from proteolytic processing of the APP protein, first by b-secretase followed by g-secretase. Based on these observations, b-secretase (BACE-1) has been identified as a promising drug target for disease-modifying therapy and has attracted significant attention from the medicinal chemistry community. BACE-1 is an aspartyl protease with a site of action inside the CNS and thus represents a challenging target. Hydroxyethylamine (HEA) transition state isosteres are well-known inhibitory motifs for aspartyl proteases, and prior work from these laboratories identified 1 (Figure 1) as a potent inhibitor of BACE-1. Whereas this compound has good enzyme potency (IC50=11 nm) and cell activity (sAPPb_NF= 29 nm), molecular weight is still high (578 Daltons) and the compound is a P-glycoprotein transporter (PGP) substrate with poor brain penetration. To improve brain-penetration properties, truncation of the structure and removal of hydrogen bond donors and acceptors was deemed necessary. One approach is to further optimize the P3-P1 portion and eliminate the hydroxyethyl amine. The work described in this report instead focuses on prime side modifications with the goal of improving potency sufficiently to allow removal of the P2P3 portion of the inhibitor. Closer examination of the X-ray crystal structure of 1 in the BACE-1 active site shows that the basic amine makes hydrogen-bond contacts to both Asp228 and the Gly34 carbonyl (Figure 2), and SAR studies have shown that primary and secondary amines are preferred over tertiary amines in this posi-

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.

Design and synthesis of potent and selective macrocyclic thrombin inhibitors

A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.