The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-b]indole-1,4-dione Analogues

Abstract

Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Moreover, intrastriatal administration of zaprinast or UK-343,664, another PDE5 inhibitor, alleviated established LI-AIMs and restored normal LTD at the corticostriatal synapse in dyskinetic 6-OHDA-lesioned rats . The findings of these studies could have important clinical implications, because compounds such as sildenafil (Boolell et al, 1996) and tadalafil (Daugan et al, 2003a(Daugan et al, , 2003b are PDE5 inhibitors currently used for treatment of erectile dysfunction that could be advanced rapidly to clinical trials.…”

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements

“…We initially attempted to improve the formation of trans-bisprehomotadalafil (trans-2a) from the trans-isomer of chloroacetamide 4 by modification of the reaction conditions for tadalafil (1). 21,22) Contrary to our expectations, only trace amounts of transbisprehomotadalafil (trans-2a) were obtained under a variety of conditions, and the HPLC retention time for this product was different from that of the previously isolated compound. Thus, considering that the isolated bisprehomotadalafil (2a) might be a cis-isomer, we devised a new synthetic route that produces both the cis-and trans-isomers of the dimeric tadalafil analogues without forming the monomeric analogues (Chart 1).…”

“…Aminoesters 9 and trans-9 were prepared according to literature procedures. 21,22) Dialkylation of amines 5a,b with bromoacetate 6 produced diester 7a,b, from which the benzyl groups were removed by hydrogenolysis to produce diacids 8a,b in high yields. 23) With these diacids 8a,b in hands, we moved next to couple them with amines 9 and trans-9.…”

First highly stereocontrolled synthesis of tetrahydro trans-β-carboline derivatives by exploiting the influence of a cyclic amide

“…Pictet-Spengler reaction were found to utilize amines, substituted amines 1,3,12,14,15,22 or carbamates 23 for β-carboline synthesis. However, in our approach, we utilized amide 15 to yield β-carboline derivatives 17a-c and 12 as shown in Scheme 4.…”

“…We were interested to work on tadlafil and its isomers and the literature search revealed that the first synthesis of tadalafil 1c was described by two groups Martin et al 11 and Daugan et al 12 Both the approaches involve cyclization of D-tryptophan methyl ester 3 with piperonal 2 using trifluoroacetic acid (TFA) in dichloromethane that afforded (1R,3R)-cis-pyrido-indole derivative 4 via isomerization (cis/trans: from 60/40 to 97/03). Thereafter, acylation of 4 with chloroacetyl chloride 5 yielded the chloroacetyl derivative 8, which was finally subjected to cyclization with methylamine in methanol to yield 1c as shown in Scheme 1.…”