Innovation in the discovery of the HIV-1 attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir

Abstract

The discovery and development of fostemsavir (2), the tromethamine salt of the phosphonooxymethyl prodrug of temsavir (1), encountered significant challenges at many points in the preclinical and clinical development program that, in many cases, stimulated the implementation of innovative solutions in order to enable further progression. In the preclinical program, a range of novel chemistry methodologies were developed during the course of the discovery effort that enabled a thorough examination and definition of the HIV-1 attachment inhibitor (AI) pharmacophore. These discoveries helped to address the challenges associated with realizing a molecule with all of the properties necessary to successfully advance through development and this aspect of the program is the major focus of this retrospective. Although challenges and innovation are not unusual in drug discovery and development programs, the HIV-1 AI program is noteworthy not only because of the serial nature of the challenges encountered along the development path, but also because it resulted in a compound that remains the first and only example of a mechanistically novel class of HIV-1 inhibitor that is proving to be very beneficial for controlling virus levels in highly treatment-experienced HIV-1 infected patients.

Keywords: Fostemsavir; HIV-1 attachment inhibitors; Indole-3-gyloxamide; Prodrug; Synthetic methodology; Temsavir.

Scheme 1

The synthetic approach utilized to explore variation of the phenyl moiety of the benzamide of 3

Scheme 2

Methodology developed for the Friedel–Crafts acylation of substituted indoles with oxalyl chloride or a monoester of oxalyl chloride

Fig. 1

A synopsis of the key SAR points associated with structural variation of indole 3-glyoxamide-based HIV-1 AIs

Scheme 3

Mono-benzoylation of the lithium dianion derived from piperazine (44) and the synthesis of unsymmetrical piperazine diamides 49 [23]

Scheme 4

Synthetic protocols for the selective acylation of unsymmetrically-substituted piperazines [24]. A Synthetic protocol for the regioselective benzoylation of 2-methylpiperazine. B Synthetic protocol for the regioselective benzoylation of 2,6-dimethylpiperazine

Scheme 5

Synthetic protocol for the mono-benzoylation of pyrrolidin-3-amine (58) [25]

Scheme 6

Synthetic protocol for the mono-benzoylation of piperazine (44) mediated by coordination of one amine moiety with 9-BBN [26]

Scheme 7

A synthetic protocol to access glyoxamides 78 by a Claisen-type condensation between an aminoacetonitrile 75 and an ester 76 followed by oxidation of the intermediate anion 77 or by the base-mediated coupling of 75 with a nitrile 79 to afford an intermediate anion 80 which was converted to 78 by an oxidative process [27, 28]

Scheme 8

A synthetic protocol developed to access heterocycle-based α-keto amides 84 [29]

Scheme 9

Synthetic protocol to access amides 88 and ketones 89 by reaction of an aminoacetonitrile 75 or a heteroarylmethyl nitrile 85 with a 2-halo heterocycle 81 followed by oxidation of the intermediate anions 86 and 87 [30, 31]

Scheme 10

A synthetic approach to the preparation of heterocycle-containing amide derivatives by sequential reaction a 2-halo heterocycle with malononitrile (90), CH₃CO₃H and an amine to afford amides 88 via the intermediacy of an acyl nitrile 92 [32]

Scheme 11

A synthetic approach developed to access heteroaryl carboxamides 88 [33]

Scheme 12

Reaction protocol for the oxidation of aminoacetonitrile derivatives 97 and capture of intermediate 98 to afford amidines 99 [34]

Fig. 2

Functional equivalences of the synthons developed to access HIV-1 AIs

Scheme 13

Methodologies devised to provide synthetic access to azaindole 3-glyoxylic acid derivatives [35, 40, 41]

Scheme 14

Mechanism of the Bartoli indole synthesis of indole (135) from nitrobenzene (126) [42, 43]

Scheme 15

Preparation of 4- and 6-azaindoles from nitropyridine derivatives using the Bartoli indole synthesis protocol [45, 46]

Scheme 16

An approach to the synthesis of azaindoles based on the Leimgruber–Batcho reaction protocol [49]

Fig. 3

Conformational flexibility and tautomerism of the indazole-based HIV AI 151 [28, 51]. A Preferred orientation of the 3-carbonyl moiety; B alternative orientation of the 3-carbonyl moiety; C intramolecular H-bonded tautomer of B

Fig. 4

Structures of 155 and 156, potential metabolites of 42 and 154, respectively

Fig. 5

Single crystal X-ray structure of mono-methyl amide 158 illustrating the intramolecular H-bond between the amide C=O and indole N–H

Fig. 6

A Intramolecular H-bond between the amide C=O and indole N–H in 158; B Allylic-1,3-type strain between the trans-methyl substituent of the dimethylamide of 159 and the C-6 proton of the indole core

Fig. 7

Intramolecular H-bonding interactions in C-7 mono-methyl carboxamide-substituted 6-azaindoles

Fig. 8

Favorable and unfavorable interactions between C-7 heterocycles and the 6-azaindole core in a series of HIV-1 AIs that stabilize or destabilize a planar topography. A Stabilization of a thiazole ring conformation by a favorable nitrogen to sulfur σ* and a thiazole nitrogen to azaindole N-H H-bond interaction; B Thiophene conformation stabilization by a favorable nitrogen to sulfur σ* interaction offset by unfavorable allylic 1,3-type strain between the thienyl 3-hydrogen atom and the azaindole N-H; C Stabilization of a C-7 azole conformation by a favorable azole C-H to azaindole nitrogen H-bonding interaction and a favorable azole nitrogen to azaindole N-H interaction; D Unfavorable allylic 1,3-type strain interaction between an azole substituent and the azaindole nitrogen atom offset by a favorable azole nitrogen to azaindole N-H interaction

Scheme 17

General synthetic approach to phosphonooxymethyl prodrugs 193–195

Scheme 18

Specific conditions for the synthesis of phosphonooxymethyl prodrug 2

Scheme 19

Elimination mechanism for the initial deprotection of the tert-butyl phosphate prodrug precursor

Scheme 20

Phosphonooxymethyl prodrug release mechanism

Scheme 21

Synthesis of the amminium prodrug of the HIV‑1 attachment inhibitor 176 [90]

Fig. 9

A An X-ray cocrystal structure of 1 bound to HIV-1 gp120 (PDB access code 5U7O). B Two dimensional plot of the key interactions between 1 and HIV-1 gp120 from an X-ray cocrystal structure